ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.428G>A (p.Arg143Gln) (rs397516209)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000168835 SCV000692498 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-03-10 criteria provided, single submitter research The MYH7 Arg143Gln variant has been identified in over 15 HCM probands and has been found to segregate in 2 families (see references; LMM, ClinVar SCV000059551.4). The variant is present as a singleton event in the Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in a HCM proband, with no family history of sudden cardiac death or disease. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, based on the number of HCM cases identified to harbour the variant, segregation, rarity in the general population and in silico tools supportive of a deleterious effect, we classify MYH7 Arg143Gln as a "likely pathogenic" variant.
Blueprint Genetics, RCV000157348 SCV000207085 pathogenic Primary familial hypertrophic cardiomyopathy 2015-05-18 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000168835 SCV000299239 pathogenic Familial hypertrophic cardiomyopathy 1 2016-06-29 criteria provided, single submitter clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000477095 SCV000564407 likely pathogenic Hypertrophic cardiomyopathy 2015-12-16 reviewed by expert panel curation The c.428G>A (p.Arg143Gln) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:15563892; PMID:15358028; PMID:21252143; PMID:20075948; PMID:21239446; PMID:22765922; PMID:24093860; Partners LMM ClinVar SCV000059551.5). This variant segregated with disease in 4 affected individuals (PP1; Partners LMM ClinVar SCV000059551.5). This variant has been identified in 1/66732 European chromosomes (PM2; http://exac.broadinstitute.org). 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 (PMID:29300372): PS4; PM2; PP1
GeneDx RCV000158731 SCV000208666 likely pathogenic not provided 2017-03-16 criteria provided, single submitter clinical testing The R143Q likely pathogenic variant in the MYH7 gene has been reported previously in association with HCM (Kimura et al., 2001; Van Driest et al., 2004; Song et al., 2005; Coto et al., 2012; Marsiglia et al., 2013). The R143Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and occurs at a position that is conserved across species. Additionally, missense variants in the same residue (R143W, R143G) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014); however, the pathogenicity of the R143G variant has not been definitively determined. Furthermore, in silico analysis is inconsistent in its predictions as to whether the R143Q variant is damaging to the protein structure/function, and functional studies have not been performed.
Invitae RCV000477095 SCV000546206 pathogenic Hypertrophic cardiomyopathy 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 143 of the MYH7 protein (p.Arg143Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397516209, ExAC <0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15358028, 15563892, 20075948, 21252143, 22765922, 24093860, 27247418, 26914223). ClinVar contains an entry for this variant (Variation ID: 43006). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg143Trp) is reported to be deleterious (PMID: 12974739, 24510615, Invitae). In addition, p.Arg143Gly is absent from population databases and has been observed in patients with hypertrophic cardiomyopathy (PMID: 12820698, 22429680). This indicates that the p.Arg143 residue is important for MYH7 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000477095 SCV000059551 likely pathogenic Hypertrophic cardiomyopathy 2018-07-03 criteria provided, single submitter clinical testing The p.Arg143Gln variant in MYH7 has been reported in 15 individuals with HCM (So ng 2005, Van Driest 2004, Wang 2007, Kimura 2010, Gruner 2011, Fokstuen 2011, Ma rsiglia 2013, Meder 2011, Coto 2012, Gomez 2014). It has also been identified by our laboratory in 6 individuals with HCM and segregated with disease in 4 affec ted relatives from 2 families. This variant has been identified in 1/111692 Euro pean chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs397516209) and has been reported in ClinVar (Variation ID : 43006). Computational prediction tools and conservation analysis suggest that the p.Arg143Gln variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg143Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2, PP1, PP3.

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