Workshop ACMG-AMP classification - Amazon S3...Workshop ACMG-AMP classification...

Workshop ACMG-AMP classification

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ACMG-AMP criteria and data sources

Population DB´s(ExAC, gnomAD, 1000G,

ESP, dbSNP…)

Internal Data(segregation, functional

studies)

Literature(PubMed, HGMD,

Google scholar)

LSDB´s(LOVD, ClinVar, UMD)

Prediction Tools(see ACMG/AMP)

Case 1 PATIENT: Male, 46 years of age.

PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family

history negative regarding mental retardation or skeletal abnormalities.

HPO-TERMS: Hypophosphatemia, Osteopenia

ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)

DETECTED VARIANT(S):

(GRCh37/hg19)

Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID

SLC9A3R1 NM_004252.4 c.328C>G

(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969

Case 1Case 1 PATIENT: Male, 46 years of age.

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

?Are these papers really valid

lines of evidence

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

Not consistent

ESP, dbSNP…)

studies)

Google scholar)

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

(GRCh37/hg19)

SLC9A3R1 NM_004252.4 c.328C>G

BS1+BS2 Class 1 – benign

Carefully interpret Literature and Database entries

It is not surprising to find a “common variant” in your patient (with a “common” phenotype)

ESP, dbSNP…)

studies)

Google scholar)

Case 2: PATIENT: Female, 38 years of age.

PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45

and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family

segregation analysis performed.

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

ANALYSED GENES: 12

(GRCh37/hg19)

CHEK2 NM_007194.3 c.470T>C

Case 2

Valid lines of conflicting evidence

ACMG-AMP system is intended for “high penetrant” mendeliangenes

ESP, dbSNP…)

studies)

Google scholar)

Maybe a new class will/ should be established:

“Pathogenic –low penetrance”

Case 3PATIENT: Male, 2 years of age.

PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.

ANALYSED GENES: 23

(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID

SLC22A5 NM_003060.3 c.1463G>A

(p.Arg488His) homozygous G A chr5:131729380

rs28383481

PATIENT: Male, 2 years of age.

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

Not consistent

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

ANALYSED GENES: 23

SLC22A5 NM_003060.3 c.1463G>A

rs28383481

BS1+BS2Class 1 –benign

ACMG-AMP for “single” variants in mendeliangenes(not digenic, not haplotypes, not trans-genomic-contextual variants)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

PATIENT: Male, 30 years of age

PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father

deceased of haemorrhagic stroke.

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

heterozygous C T chr13:110827696

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

heterozygous C T chr13:110827696 -

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

heterozygous C T chr13:110826268 rs778978790

ESP, dbSNP…)

studies)

Google scholar)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

No information

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

Alteration of Glycinin “Collagen triple helix repeat” domain

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

Expert Opinion:

Move „PM1“ to

„Strong“

1 Strong + PM2+ PP3 = Class 4

Otherwise: PM1 + PM2 +PP3 = Class 3 VUS

Biology: virtually all described

pathogenic variants in COL4A1

(and COL4A2) alter Glycin

residues in the „Collagen“

domain of the protein

Case 4

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

ESP, dbSNP…)

studies)

Google scholar)

Case 4

No information

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

When a variant is observed in a case with a clear alternate

genetic cause of disease, this is generally considered

supporting evidence to classify the variant as benign.

Case 4

BP4+BP5 = class 2

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

benign

Case 4

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

rs778978790

ANALYSED GENES: 22

(GRCh37/hg19)

COL4A1 NM_001845.5 c.3067G>A

(p.Gly1023Arg)

COL4A1 NM_001845.5 c.3484G>A

(p.Ala1162Thr)

ESP, dbSNP…)

studies)

Google scholar)

For certain genes / diseases with a special “biology” expert knowledge helps for proper interpretation(COLx-genes; NOTCH3 (Cys); RB1; Muscle genes, …)

Don’t hesitate to consult an expert (e.g. LSDB curators, scientific meetings, literature, private “network”)

PATIENT: Female, 46 years of age.

PHENOTYPE: Astrocytoma at 10 years of age, breast

cancer at 29 years of age, colorectal cancer

at 39 years of age, kidney cancer at 45 years

of age. Microsatellite stable with expression

of all mismatch repair genes.

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573

FH NM_000143.3 c.1431_1433dup

(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046

Case 5PATIENT: Female, 46 years of age.

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

PS3+PM2+PM5+PP1+PP3 = class 5

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

Described in several patients with

recessive FHD in compound

heterozygous state with LOF variants

Segregates with disease (FHD)6. Deschauer (2006) Mol Genet Metab. 88: 146 PubMed: 16510303

7. Ezgu (2013) Gene. 25: 403 PubMed: 23612258

8. Pollard (2005) Hum Mol Genet. 14: 2231 PubMed: 15987702

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

Functional studies demonstrate that

a compound heterozygous state of

c.1431_1433dup with LOF variant

cause a significant reduction of FH

activity

Phenotype (FHD) is highly specific

for LOF in the FH gene

6. Deschauer (2006) Mol Genet Metab. 88: 146 PubMed: 16510303

7. Ezgu (2013) Gene. 25: 403 PubMed: 23612258

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

Found in patients with RCC and/ or

Leiomyoma as well as in controls

6. Deschauer (2006) Mol Genet Metab. 88: 146 PubMed: 16510303

7. Ezgu (2013) Gene. 25: 403 PubMed: 23612258

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

Protein length change (in-frame

indel) in a non-repeat region

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

Summary of ACMG-AMP criteria:

• PS3: functional study shows FD (FHD and HLRCC)• PM3: detected in trans with pathogenic for recessive disease (FHD)• PM4: protein length change in non-repeat region (FHD and HLRCC)• PP1: co-segregation with disease (FHD)• PP4: phenotype is highly specific (FHD) • BS1: allele frequency greater than expected (FHD and HLRCC)• BS2: observed in healthy adult homoz. (for AR, eaerly onset) (FHD)

PS3 + PM3 + PM4 + PP1 + PP4 (BS1/BS2) = class 5 for FHD

PS3 + PM4 (BS1) = class 4 (reduced penetrance) for HLRCC

• Valid but conflicting lines of evidence

• Reduced / Low penetrance

• Two loss-of-function variants would be lethal (complete FHD)

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ANALYSED GENES: 94

TP53 NM_000546.5 c.722C>T

FH NM_000143.3 c.1431_1433dup

ESP, dbSNP…)

studies)

Google scholar)

Pathogenic, but with reduced penetrance

Relevant Phenotype:

• (Kidney) Cancer, not FH-Deficiency

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