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]

Variant: NM_000257.4(MYH7):c.2606G>A (p.Arg869His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA012723

177667 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 10a62d23-9dad-468c-a363-8c26ffef1bb5

Approved on: 2021-09-28

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.2606G>A

NM_000257.4(MYH7):c.2606G>A (p.Arg869His)

NC_000014.9:g.23424842C>T

CM000676.2:g.23424842C>T

NC_000014.8:g.23894051C>T

CM000676.1:g.23894051C>T

NC_000014.7:g.22963891C>T

NG_007884.1:g.15820G>A

ENST00000355349.4:c.2606G>A

ENST00000355349.3:c.2606G>A

NM_000257.3:c.2606G>A

Likely Pathogenic

PM1 PM2_Supporting PP1_Moderate PS4

PP3 PP2 PM6 PM4 PM5 BA1 BS2 BS4 BS3 BS1 PVS1 BP5 BP2 BP7 BP4 BP3 BP1 PS3 PS2 PS1

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.2606G>A (p.Arg869His) variant has been identified in >30 individuals with HCM, including at least 2 individuals with an additional variant in another gene that may contribute to their disease (PS4; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Cecchi 2006 PMID: 17180650; Olivotto 2008 PMID: 18533079; Girolami 2010 PMID: 20359594; Olivotto 2011 PMID: 21835430; Witjas-Paalberends 2013 PMID: 23674513; Marsiglia 2013 PMID: 24093860; Bos 2014 PMID: 24793961; Coppini 2014 PMID: 25524337; Adalsteinsdottir 2014 PMID: 25078086; Homburger 2016 PMID: 27247418; Viswanathan 2017 PMID: 29121657; Walsh 2017 PMID: 2753225; Ho 2018 PMID: 30297972; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 6 affected relatives with HCM from at least two families (PP1_Moderate; Girolami 2010 PMID: 20359594; GeneDx pers. comm.). Additionally, this variant has also been reported in 1 individual with DCM with an additional variant in another gene that may contribute to their disease, 1 individual with LVH and suspected HCM, 1 individual with LVNC, 1 individual with septal hypertrophy with AV conduction defect, and 4 individuals with unspecified heart disease (Ambry pers. comm.; GenDx pers. comm.). This variant was identified in 0.002% (FAF 95% CI; 2/16254) of African chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but has also been identified in a greater number of African chromosomes in gnomAD v.3.1. Therefore, the PM2 criterion was downgraded to PM2_supporting. 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 (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM2_Supporting, PM1.

PM1

This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372).

PM2_Supporting

Variant was identified in 6/251440 (0.002%) of alleles tested from presumed healthy individuals in the Genome Aggregation Database (gnomAD), including 0.01% of African alleles (Popmax filtering allele frequency: 0.002%), but has also been identified in a greater number of African chromosomes in gnomAD v.3.1. Therefore, the PM2 criterion was downgraded to PM2_supporting.

PP1_Moderate

This variant was found to segregate with disease in 6 individuals from 2 different families (PMID 20359594, internal laboratories data from the ClinGen CMP working group).

PS4

This variant was observed in > 15 individuals with HCM

PP3

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) gave conflicting results with regards to a possible impact on the protein function and/or structure.

PP2

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

PM6

no de novo cases

PM4

Missense variant

PM5

CHEO has previously reported p.Arg869Cys as likely pathogenic in Nov 2019. As per our CHEO internal rules, we apply PM5 if variant classified by us as LP or P within the last year. Not met because only applies to P variants. variant in same codon is LP at best

BA1

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

BS2

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

BS4

n/a

BS3

no experimental data available

BS1

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

PVS1

missense variant

BP5

not applicable here

BP2

not observed

BP7

missense variant

BP4

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

BP3

Missense variant

BP1

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

PS3

no experimental data available

PS2

no de novo cases

PS1

n/a

Curation History

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