ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2129C>A (p.Pro710His)

dbSNP: rs727504272
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000469589 SCV001976467 likely pathogenic Hypertrophic cardiomyopathy 2021-09-28 reviewed by expert panel curation 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, 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
Invitae RCV000469589 SCV000546274 pathogenic Hypertrophic cardiomyopathy 2023-12-04 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 710 of the MYH7 protein (p.Pro710His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22555271, 23054336, 25611685, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177734). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002415654 SCV002728993 likely pathogenic Cardiovascular phenotype 2024-02-15 criteria provided, single submitter clinical testing The p.P710H variant (also known as c.2129C>A), located in coding exon 17 of the MYH7 gene, results from a C to A substitution at nucleotide position 2129. The proline at codon 710 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Kindel SJ et al. J Card Fail, 2012 May;18:396-403; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ko C et al. Genet Med, 2018 01;20:69-75). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154344 SCV000204007 uncertain significance not specified 2017-04-12 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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