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.2602G>C (p.Ala868Pro)

Curation Version - 1.0
Curation History
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CA012698

177847 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0af1a519-33cd-4d4e-bb6f-52f2540ca538

Approved on: 2021-09-28

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.2602G>C

NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro)

NC_000014.9:g.23424846C>G

CM000676.2:g.23424846C>G

NC_000014.8:g.23894055C>G

CM000676.1:g.23894055C>G

NC_000014.7:g.22963895C>G

NG_007884.1:g.15816G>C

ENST00000355349.4:c.2602G>C

ENST00000355349.3:c.2602G>C

NM_000257.3:c.2602G>C

Likely Pathogenic

PP3 PM1 PM2 PS4_Moderate

BP4 PS1 PS3 PP1 PM5 BS3

Evidence Links 1

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.2602G>C (p.Ala868Pro) variant has been identified in at least 13 probands with HCM (PM4_Moderate; Millat 2010 PMID:20624503; Millat 2010 PMID:20800588; Walsh 2017 PMID: 27532257; Ambry pers. comm., GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.). Additionally, this variant was reported in a patient with suspected RCM/HCM as well as arrhythmia, who also carried the pathogenic NM_000257.4(MYH7):c.2167C>T p.(Arg723Cys) variant. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://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 (PM1; Walsh 2017 PMID:27532257). 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): PM4_Moderate, PM2, PM1, PP3.

PP3

Deleterious by multiple protein predictors. REVEL score is 0.879 which is greater than the impact threshold of > 0.75; SIFT as listed in Alamut is Tolerated

PM1

Missense variants between amino acids 181-937 PMID: 27532257

mutation hotspot in between amino acids 181-937 in MYH7 PubMed:27532257

PM2

Absent from gnomAD (sufficient coverage), ExAC, 1000 Genomes, & ESP

PS4_Moderate

>=6 probands so PS4_Moderate. Total of 7 probands with HCM and with no other VUS variants in cardiomyopathy genes: OMGL - 1 HCM, LMM - 1 HCM, Invitae - 1 HCM with no additional variants, GeneDx - 1 HCM with no additional variants, Ambry - 2 HCM so total from Clinical Labs is 6 individuals diagnosed with HCM. From the literature: PMID: 20624503 - 1 HCM patient. Could also cite PMID: 27532257 for the LMM and OMGL HCM probands.

BP4

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

PS1

No other variants at this codon

PS3

No published experimental studies

PP1

See GeneDx internal data; insufficient to count as segregation

PM5

No other variants at this codon

BS3

No published experimental studies

Curation History

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