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

Variant: NM_000257.4(MYH7):c.2129C>A (p.Pro710His)

CA011747

177734 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6d86aae9-6974-4abd-87ec-315566fe779c
Approved on: 2021-09-28
Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.2129C>A
NM_000257.4(MYH7):c.2129C>A (p.Pro710His)
ENST00000355349.4:c.2129C>A
ENST00000355349.3:c.2129C>A
NM_000257.3:c.2129C>A
NC_000014.9:g.23425997G>T
CM000676.2:g.23425997G>T
NC_000014.8:g.23895206G>T
CM000676.1:g.23895206G>T
NC_000014.7:g.22965046G>T
NG_007884.1:g.14665C>A
More

Likely Pathogenic

Met criteria codes 4
PM1 PM2 PS4_Moderate PP3
Not Met criteria codes 13
PM6 PM5 BA1 BS4 BS3 BS1 BP5 BP2 BP4 PS2 PS1 PS3 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4(MYH7):c.2129C>A (p.Pro710His) variant has been identified in in at least 7 individuals with HCM (PM4_Moderate; Kindel 2012 PMID:22555271; Miller 2013 PMID:23054336; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant was also observed to segregated with HCM in 1 affected relative (LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. 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): PS4_Moderate, PM2, PM1, PP3
Met criteria codes
PM1
Missense variant located in the head domain (codons 181-937; Walsh et al. PMID: 27532257)
PM2
Variant absent in GnomAD. Region with good coverage (250K) 10/22/2020
PS4_Moderate
Variant has been identified in at least 7 individuals: 1 from Miller et al, 2013 (PMID:23054336) and 6 from internal laboratory data: 3 individuals with HCM from GeneDx, 1 individual with HCM from the Laboratory of Molecular Medicine (LMM), 1 individual with HCM from the Oxford Molecular Genetics Laboratory (OMGL) and 1 individual with HCM from Invitae Variant has been identified in at least 7 individuals with HCM (PM4_Moderate; Kindel 2012 PMID:22555271; Miller 2013 PMID:23054336; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant was also observed to segregated with HCM in 1 affected relative (LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1.
PP3
Predicted to be damaging by in- silico programs (SIFT, PolyPhen, Provean). Findings consistent with REVEL
Not Met criteria codes
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
P710R and P710L present in HGMD, however their classification does not reach pathogenic
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Only one segregation reported by LMM
Curation History
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