Submissions for variant NM_000257.4(MYH7):c.1447G>A (p.Glu483Lys)

gnomAD frequency: 0.00001  dbSNP: rs121913651

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539828	SCV000623642	pathogenic	Hypertrophic cardiomyopathy	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 483 of the MYH7 protein (p.Glu483Lys). This variant is present in population databases (rs121913651, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10424815, 24111713, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14119). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804733	SCV002050807	pathogenic	Cardiomyopathy	2021-12-07	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1447G>A (p.Glu483Lys) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes (gnomAD). c.1447G>A has been reported in the literature in multiple individuals affected with Cardiomyopathy (examples: Richard_1999, Berge_2013 and Walsh_2017) . These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV002247341	SCV002517756	pathogenic	MYH7-related skeletal myopathy	2022-05-04	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000015176	SCV002522187	likely pathogenic	Hypertrophic cardiomyopathy 1	2021-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390109	SCV002700795	pathogenic	Cardiovascular phenotype	2024-02-28	criteria provided, single submitter	clinical testing	The p.E483K pathogenic mutation (also known as c.1447G>A), located in coding exon 13 of the MYH7 gene, results from a G to A substitution at nucleotide position 1447. The glutamic acid at codon 483 is replaced by lysine, an amino acid with similar properties. 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 was detected in a family with hypertrophic cardiomyopathy (HCM) where it occurred alone in four affected individuals and co-occurred with an MYBPC3 alteration in two affected individuals with more significant hypertrophy (Richard P et al. J. Med. Genet., 1999 Jul;36:542-5). This variant has also been detected in multiple additional individuals from HCM cohorts (Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001804733	SCV004239436	pathogenic	Cardiomyopathy	2023-01-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000539828	SCV004839123	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 483 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. 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). Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10424815, 12797239, 24111713, 24704860, 25351510, 27532257, 28378410, 33495596, 33495597). It has been shown that this variant segregates with disease in multiple individuals from one family (PMID: 10424815). Some of these individuals also carried a pathogenic variant in the MYBPC3 gene that could explain the observation of a more severely affected phenotype (PMID: 10424815). This variant has been identified in 2/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000539828	SCV004848505	likely pathogenic	Hypertrophic cardiomyopathy	2019-10-14	criteria provided, single submitter	clinical testing	The p.Glu483Lys variant in MYH7 has been reported in 5 individuals with HCM (Richard 1999, Berge 2014, Walsh 2017). One of these individuals also carried a nonsense variant in MYBPC3. Her affected son carried both variants and 4 additional affected family members carried only the p.Glu483Lys variant in MYH7. The proband and her son were reported to be more severely affected than family members carring either the MYH7 or MYBPC3 variant in isolation (Richard 1999). It has also been identified in 2/129164 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID# 14119). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Supporting, PP1.
GeneDx	RCV004589514	SCV005080555	likely pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Reported in association with HCM in published literature (PMID: 24111713, 10424815, 12707239, 25351510, 27532257, 35653365); Identified in several individuals with HCM from a single large family; a few individuals also have a pathogenic nonsense variant in the MYBPC3 gene and the individuals with both variants were described as showing a greater degree of hypertrophy than those with only one variant (PMID: 10424815, 12707239); 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: 22874472, 34495297, 35753512, 12110947, 28606303, 18761664, 35653365, 25351510, 12707239, 27532257, 29300372, 10424815, 24111713)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015176	SCV005398241	pathogenic	Hypertrophic cardiomyopathy 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the myosin motor domain (NCBI, UniProt, PMID 29300372). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in at least ten individuals with HCM, and has sometimes been observed in a compound heterozygous state or in addition to another heterozygous variant, resulting in a more severe phenotype (Atlas of Cardiac Genetic Variation, ClinVar, HGMD, LOVD, PMIDs: 10424815, 24111713, 27532257 & 28378410). (SP) 0902 - This variant has moderate evidence for segregation with disease. The variant was shown to segregate with HCM over three generations in one family, with four affected heterozygotes, and an additional two heterozygotes with a more severe phenotype who also carried a pathogenic variant in the MYBPC3 gene (PMID: 10424815). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000015176	SCV005685419	likely pathogenic	Hypertrophic cardiomyopathy 1	2024-09-23	criteria provided, single submitter	clinical testing	The MYH7 c.1447G>A (p.Glu483Lys) variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy and is reported to segregate with disease in six individuals in one family (Berge KE and Leren TP, PMID: 24111713; Richard P et al., PMID: 10424815; Walsh R et al., PMID: 27532257). Two of those individuals also harbored a pathogenic variant in MYBPC3 and displayed more severe hypertrophy than those with the MYH7 c.1447G>A variant alone (Richard P et al., PMID: 10424815). This variant is only observed on 2/282,856 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant resides within the myosin motor domain of MYH7 that is defined as a critical functional domain and is significantly overrepresented in individuals with hypertrophic cardiomyopathy (Walsh R et al., PMID: 27532257). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MYH7 function. This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by nine submitters and a variant of uncertain significance by one submitter. Based on available information, the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, this variant is classified as likely pathogenic.
OMIM	RCV000015176	SCV000035433	pathogenic	Hypertrophic cardiomyopathy 1	1999-07-01	no assertion criteria provided	literature only
Genetics and Genomics Program, Sidra Medicine	RCV000539828	SCV001434145	uncertain significance	Hypertrophic cardiomyopathy		flagged submission	research