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.5342G>A (p.Arg1781His)

CA015985

43064 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7f87264e-0238-497f-84ef-902ccd67f99c
Approved on: 2021-08-25
Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.5342G>A
NM_000257.4(MYH7):c.5342G>A (p.Arg1781His)
ENST00000355349.4:c.5342G>A
ENST00000355349.3:c.5342G>A
NM_000257.3:c.5342G>A
NC_000014.9:g.23415212C>T
CM000676.2:g.23415212C>T
NC_000014.8:g.23884421C>T
CM000676.1:g.23884421C>T
NC_000014.7:g.22954261C>T
NG_007884.1:g.25450G>A
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Uncertain Significance

Met criteria codes 3
PS4_Moderate PM2 PP3
Not Met criteria codes 10
BS4 BS3 BP4 PS2 PS1 PS3 PM6 PM1 PM5 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.5342G>A (p.Arg1781His) variant in MYH7 has been identified in at least 12 individuals with HCM (PS4_Moderate; Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). This variant was identified in 0.00116% (FAF 95% CI; 2/30616) of South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3.
Met criteria codes
PS4_Moderate
in at least 12 probands with HCM (Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm)
PM2
In gnomAD, 2/30616 alleles in South Asian, FAF is 0.00116%
PP3
Most predictors trending deleterious, but several right at the threshold, including REVEL which is at threshold of 0.75. Arginine is highly conserved across mammals (UCSC Genome Browser Multiz alignment).
Not Met criteria codes
BS4
No segregation data
BS3
No evidence
BP4
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
PS3
No evidence
PM6
No de novo data
PM1
Variant is located outside the hotspot domain.
PM5
p.Arg1781Cys is absent from ExAC and observed in 3 HCM probands in the literature; currently 2* VUS in ClinVar
PP1
No segregation data
Curation History
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