Submissions for variant NM_000257.4(MYH7):c.4145G>A (p.Arg1382Gln)

gnomAD frequency: 0.00001  dbSNP: rs727504325

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000560763	SCV000204083	likely pathogenic	Hypertrophic cardiomyopathy	2018-09-12	criteria provided, single submitter	clinical testing	The p.Arg1382Gln variant in MYH7 has been identified in at least 15 individuals with HCM (Nunez 2013, Zou 2013, Walsh 2017, Kassem 2017, Ambry pers. comm., Invi tae pers. comm., GeneDx pers. comm., LMM data). It has also been reported by oth er clinical laboratories in ClinVar (Variation ID 177788) and has been identifie d in 1/15304 of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservati on analysis do not provide strong support for or against an impact to the protei n. In summary, although additional studies are required to fully establish its c linical significance, the p.Arg1382Gln variant is likely pathogenic. ACMG/AMP Cr iteria applied: PS4, PM2.
GeneDx	RCV000766456	SCV000616801	likely pathogenic	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 27247418, 23782526, 23283745, 27532257, 24047955, 30972196, 31513939, 25132132, 28687478, 31941943, 31447099, 33673806, 28606303)
Invitae	RCV000560763	SCV000623715	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1382 of the MYH7 protein (p.Arg1382Gln). This variant is present in population databases (rs727504325, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 23782526, 25132132, 27532257, 30972196, 31513939, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 177788). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000620123	SCV000736234	likely pathogenic	Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	The p.R1382Q variant (also known as c.4145G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4145. The arginine at codon 1382 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM) (Núñez L et al. Circ. J. 2013; 77(9):2358-65; Zou Y et al. Mol. Biol. Rep. 2013 Jun; 40(6):3969-76; Kassem HS et al. Egyptian J of Med Hum Genet. 2017; 18:381-387; Walsh R et al. Genet. Med. 2017;19:192-203; García-Molina E et al. Am J Transl Res, 2019 Mar;11:1724-1735; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). A likely pathogenic alteration at the same codon, p.R1382W (c.4144C>T), has also been described in association with HCM (Richard P et al. Circulation 2003; 107(17):2227-32). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Human Genetics, University of Leuven	RCV000560763	SCV000886837	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000766456	SCV000927533	likely pathogenic	not provided	2018-02-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177330	SCV001341525	likely pathogenic	Cardiomyopathy	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1382 in the LMM domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 28687478, 30972196, 31941943, 33673806, Kassem 2017, Luo et al., 2019; communication with an external laboratory; ClinVar Variation ID: 177788). This variant has been identified in 1/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766456	SCV001715066	uncertain significance	not provided	2019-08-03	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002287373	SCV002578123	likely pathogenic	not specified	2022-09-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766456	SCV003815403	uncertain significance	not provided	2021-01-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177330	SCV004239465	likely pathogenic	Cardiomyopathy	2023-04-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917511	SCV004742320	uncertain significance	MYH7-related condition	2023-12-19	criteria provided, single submitter	clinical testing	The MYH7 c.4145G>A variant is predicted to result in the amino acid substitution p.Arg1382Gln. This variant has been reported in the heterozygous state in ten individuals with hypertrophic cardiomyopathy (HCM) (Nunez et al. 2013. PubMed ID: 23782526; Zou et al. 2013. PubMed ID: 23283745; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; García-Molina et al. 2019. PubMed ID: 30972196; Table S2, Robyns et al. 2020. PubMed ID: 31513939; Additional File 2, Hathaway et al. 2021. PubMed ID: 33673806). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. In an updated version of the gnomAD this variant is reported in 0.036% of alleles in individuals of Middle Eastern descent (https://gnomad.broadinstitute.org/variant/14-23418234-C-T?dataset=gnomad_r4) which may be too common to be a cause of disease (Kelly et al. 2018. PubMed ID: 29300372). In ClinVar, this variant has conflicting interpretations of pathogenicity, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/177788/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.