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

gnomAD frequency: 0.00001  dbSNP: rs397516209

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen 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
Laboratory for Molecular Medicine, Mass General Brigham 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.
Blueprint Genetics	RCV000157348	SCV000207085	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000158731	SCV000208666	likely pathogenic	not provided	2024-05-30	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and in published literature (PMID: 22765922, 8533830, 11433818, 15358028, 15563892, 21511876, 21239446, 22455086, 24093860, 25351510, 37466024); Not observed at significant frequency in large population cohorts (gnomAD); Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (PMID: 27532257, 29300372); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24093860, 20075948, 8533830, 33673806, 15358028, 15563892, 21511876, 22455086, 25351510, 21252143, 21239446, 27247418, 26914223, 11433818, 27532257, 29300372, 25342278, 18383048, 33487615, 31424582, 23283745, 26656175, 27054166, 28408708, 32894683, 34542152, 35653365, 34726536, 36902152, 34076677, 22765922, 38582613, 36243179, 37466024, 37652022, 37907184)
Center for Medical Genetics Ghent, University of Ghent	RCV000168835	SCV000299239	pathogenic	Hypertrophic cardiomyopathy 1	2016-06-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477095	SCV000546206	pathogenic	Hypertrophic cardiomyopathy	2024-12-24	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 143 of the MYH7 protein (p.Arg143Gln). This variant is present in population databases (rs397516209, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 20075948, 21252143, 22765922, 24093860, 26914223, 27247418). ClinVar contains an entry for this variant (Variation ID: 43006). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg143 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12820698, 12974739, 22429680, 24510615; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000168835	SCV000692498	likely pathogenic	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV002326728	SCV000987454	pathogenic	Cardiovascular phenotype	2022-06-17	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000168835	SCV000993574	likely pathogenic	Hypertrophic cardiomyopathy 1	2019-03-27	criteria provided, single submitter	research
3billion	RCV000168835	SCV002058247	likely pathogenic	Hypertrophic cardiomyopathy 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043006, PS1_S). A different missense change at the same codon (p.Arg143Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000164401, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.803, 3CNET: 0.938, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002326728	SCV002631811	likely pathogenic	Cardiovascular phenotype	2025-03-06	criteria provided, single submitter	clinical testing	The p.R143Q variant (also known as c.428G>A), located in coding exon 3 of the MYH7 gene, results from a G to A substitution at nucleotide position 428. The arginine at codon 143 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported multiple times in hypertrophic cardiomyopathy (HCM) cohorts (e.g., Song L et al. Clin. Chim. Acta. 2005;351:209-16; Meder B et al. Circ Cardiovasc Genet. 2011;4:110-22; Coto E et al. J Mol Diagn. 2012;14:518-24; Marsiglia JD et al. Am. Heart J. 2013;166:775-82; Bottillo I et al. Gene. 2016;577:227-35; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496545	SCV002805347	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-08-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149623	SCV003838772	pathogenic	Cardiomyopathy	2021-08-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158731	SCV004238299	likely pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000158731	SCV005199407	likely pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000168835	SCV005399405	likely pathogenic	Hypertrophic cardiomyopathy 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous; however, a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg143Trp): 7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin head domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by the ClinGen Expert Panel and has been reported in more than 20 individuals with HCM (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000168835	SCV005418200	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PS4+PP1
Color Diagnostics, LLC DBA Color Health	RCV003149623	SCV006061584	pathogenic	Cardiomyopathy	2024-08-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 143 in the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 50 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 21252143, 22765922, 24093860, 26914223, 27247418, 27532257, 28408708, 28615295, 33495596, 33495597, 33673806, 33782553, 37907184). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 37907184; ClinVar SCV000059551.6). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg143Trp, is considered to be disease-causing (ClinVar variation ID: 164401), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Pathogenic.