Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

CA011779

14104 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7b17a8bd-b169-46a1-8efa-b7388c4ecdef

HGVS expressions

NM_000257.3:c.2155C>T

NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

NC_000014.9:g.23425971G>A

CM000676.2:g.23425971G>A

NC_000014.8:g.23895180G>A

CM000676.1:g.23895180G>A

NC_000014.7:g.22965020G>A

NG_007884.1:g.14691C>T

NM_000257.4:c.2155C>T

ENST00000355349.3:c.2155C>T

Pathogenic

PP1_Strong PS4 PS2 PS3 PP3 PM2 PM5 PM1

Evidence Links 11

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2155C>T (p.Arg719Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; PMID:22429680; PMID:23816408; PMID:12707239; PMID:19645038; PMID:27532257; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059419.5 ), including 1 de novo occurrence (PS2; 10957787). This variant was found to segregate with disease in 8 affected family members (PP1_Strong; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; SHaRe consortium, PMID: 30297972). A mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:24829265). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2156G>A p.Arg719Gln - Variation ID 14107). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS2; PS3; PS4; PP1_ Strong; PM1; PM2; PM5; PP3

PP1_Strong

8 segregations (including SHaRe data)

Variant segregated with disease in 1 affected family member PubMed:8282798

Variant segregated with disease in 4 affected family members PubMed:9829907

Variant segregated with disease in 1 affected family member PubMed:12974739

Variant segregated with disease 1 affected family member PubMed:9822100

PS4

>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5)

Variant identified in 1 proband with HCM PubMed:23816408

Variant identified in 1 proband with HCM PubMed:19645038

Variant identified in 4 probands with HCM PubMed:27532257

Variant identified in 1 proband with HCM PubMed:12707239

Variant identified in 4 probands with HCM PubMed:8282798

Variant identified in 1 proband with HCM PubMed:22429680

Variant identified de novo in 1 proband with HCM PubMed:10957787

Variant identified in 1 proband with HCM PubMed:12974739

Variant identified in 1 proband with HCM PubMed:9822100

PS2

1 de novo occurrence with paternity confirmed

De novo occurrence with paternity confirmed PubMed:10957787

PS3

Mice heterozygous for the R719W variant develop progressive concentric hypertrophy. Homozygous mice died within 9 days of birth.

Mice heterozygous for the R719W variant develop progressive concentric hypertrophy. Homozygous mice died within 9 days of birth. PubMed:24829265

PP3

Tools predict damaging

PM2

Absent from ExAC

PM5

c.2156G>A (p.Arg719Gln) - Variation ID 14107 - Pathogenic by Expert Panel

PM1

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated PubMed:27532257

Approved on: 2016-12-15

Published on: 2018-11-16

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