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_000257.4(MYH7):c.2608C>T (p.Arg870Cys)

CA012732

161326 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 59bad543-333c-4d6f-b5d0-21a40136c576

HGVS expressions

NM_000257.4:c.2608C>T

NM_000257.4(MYH7):c.2608C>T (p.Arg870Cys)

NC_000014.9:g.23424840G>A

CM000676.2:g.23424840G>A

NC_000014.8:g.23894049G>A

CM000676.1:g.23894049G>A

NC_000014.7:g.22963889G>A

NG_007884.1:g.15822C>T

ENST00000355349.4:c.2608C>T

ENST00000355349.3:c.2608C>T

NM_000257.3:c.2608C>T

Likely Pathogenic

PS4 PP3 PM5 PM2

PS3 PS2 PS1 PP1 PM6 PM1 BS3 BP4

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.2608C>T (p.Arg870Cys) variant has been reported in >15 individuals with HCM (PS4; Anan 2000 PMID:10862102; Woo 2003 PMID:12975413; Uchiyama 2009 PMID:19149795; Funada 2010 PMID:20975235; Otsuka 2012 PMID:22112859; Fujita 2013 PMID: 24621997; Wang 2014 PMID:25132132; Mademont-Soler 2017 PMID:28771489; Hayashi 2018 PMID:29907873; Mak 2018 PMID:30022097; Inagaki 2018 PMID:30206291; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in 2 affected individual with HCM from 2 families (Otsuka 2011 PMID 22112859; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was identified in 0.0007% (FAF 95% CI; 3/113730) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.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 associated with HCM (Walsh 2017 PMID:27532257). Additionally, a different pathogenic missense variant has been previously identified at this codon which indicates that this residue may be critical to the function of the protein (PM5; NM_000257.4(MYH7):c.2609G>A (p.Arg870His) - Variation ID 14120). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PM2, PM5, PP3.

PS4

The NM_000257.4(MYH7):c.2608C>T (p.Arg870Cys) variant has been reported in >15 individuals with HCM (PS4; Anan 2000 PMID:10862102; Woo 2003 PMID:12975413; Uchiyama 2009 PMID:19149795; Funada 2010 PMID:20975235; Otsuka 2012 PMID:22112859; Fujita 2013 PMID: 24621997; Wang 2014 PMID:25132132; Mademont-Soler 2017 PMID:28771489; Hayashi 2018 PMID:29907873; Mak 2018 PMID:30022097; Inagaki 2018 PMID:30206291; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). LITERATURE: Anan 2000 PMID:10862102 - 1 proband with HCM Woo 2003 PMID:12975413 - 1 proband with HCM Uchiyama 2009 PMID:19149795 - 1 individual with HCM Funada 2010 PMID:20975235 - 1 proband with HCM Otsuka 2012 PMID:22112859 - 1 Japanese proband with HCM and segregated in 1 affected relative with HCM (Figure 1C - Family CM1696) Fujita 2013 PMID: 24621997 - 1 proband with HCM Wang 2014 PMID:25132132 - 1 (presumed Chinese) proband with HCM, Supp Table 1 Mademont-Soler 2017 PMID:28771489 - 1 proband with HCM (1 yo) that also carried a novel TTN missense variant (c.8920A>G p.M2974V) considered by the authors to be a VUS. No affected relatives were tested. Hayashi 2018 PMID:29907873 - 1 infant with HCM Mak 2018 PMID:30022097 - 1 Chinese proband with HCM from WES Inagaki 2018 PMID:30206291 - 1 individual with HCM CASES NOT COUNTED: Alfares 2015 PMID:25611685 - Reported in 2 individuals, but no phenotype information provided Amendola 2015 PMID: 25637381 - 1 individual from EVS with this variant, but no phenotype information provided Homburger 2016 PMID: 27247418 - 1 proband in SHaRe registry, but no phenotype information provided Walsh 2017 PMID:27532257 - Recites LMM data from Alfares paper (2 probands)

PP3

Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Sarcomere Polyphen is a NoCall. Conserved in mammals, but 3 fish species have a Lys at this position.

PM5

NM_000257.4(MYH7):c.2609G>A (p.Arg870His) ClinVar Variation ID: 14120 Classified as Pathogenic by expert panel in Dec 2016 NM_000257.4(MYH7):c.2609G>T (p.Arg870Leu) ClinVar Variation ID: 235031 Currently classified as 1* VUS

PM2

This variant was identified in 0.0007% (FAF 95% CI; 3/113730) of European chromosomes in gnomAD v2.1.1 (PM2, https://gnomad.broadinstitute.org/).

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS2

No de novo data

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP1

1 segregations with HCM (LMM ClinVar SCV000203913) 1 segregations with HCM (Otsuka 2011 PMID 22112859) Insufficient for PP1_Supporting

PM6

No de novo data

PM1

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; Walsh 2017 PMID:27532257). However, since PM5 is applied, this code cannot be combined with PM5.

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-11-30

Published on: 2021-12-09

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