Submissions for variant NM_000257.4(MYH7):c.4817G>A (p.Arg1606His)

gnomAD frequency: 0.00001  dbSNP: rs373514686

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035933	SCV000059584	uncertain significance	not specified	2019-08-02	criteria provided, single submitter	clinical testing	The p.Arg1606His variant in MYH7 has been reported in 8 individuals with HCM (Marsiglia 2013, Helms 2014, Bos 2014, Lopes 2015, Walsh 2017, LMM data), one of whom carried a pathogenic variant in MYH7 that was sufficient to cause disease (LMM data). This variant has also been reported in ClinVar (Variation ID 43039) and in 0.007% (9/126718) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1606His variant is uncertain. ACMG/AMP Criteria Applied: PP3
GeneDx	RCV000766463	SCV000208607	uncertain significance	not provided	2020-02-20	criteria provided, single submitter	clinical testing	Reported in association with hypertrophic cardiomyopathy (Marsiglia et al., 2013; Bos et al., 2014; Lopes et al., 2015; Homburger et al., 2016; Walsh et al., 2017; Mademont-Soler et al., 2017); Reported in ClinVar (ClinVar Variant ID# 43039; Landrum et al., 2016); 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: 27247418, 24093860, 28771489, 25351510, 24793961, 25031304, 27532257)
Invitae	RCV000475488	SCV000546266	uncertain significance	Hypertrophic cardiomyopathy	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1606 of the MYH7 protein (p.Arg1606His). This variant is present in population databases (rs373514686, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 24093860, 25031304, 25351510, 27247418, 27532257, 28771489). ClinVar contains an entry for this variant (Variation ID: 43039). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000619414	SCV000739973	uncertain significance	Cardiovascular phenotype	2022-11-04	criteria provided, single submitter	clinical testing	The p.R1606H variant (also known as c.4817G>A), located in coding exon 32 of the MYH7 gene, results from a G to A substitution at nucleotide position 4817. The arginine at codon 1606 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Marsiglia JD et al, Am. Heart J. 2013; 166(4):775-82; Helms AS et al, Circ Cardiovasc Genet 2014; 7(4):434-43; Lopes LR et al, Heart 2015; 101(4):294-301; Ho CY et al. Circulation. 2018;138(14):1387-1398). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al, Circ Cardiovasc Genet 2013 Aug; 6(4):337-46). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000627158	SCV000748009	uncertain significance	Primary familial hypertrophic cardiomyopathy	2017-06-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769443	SCV000900836	uncertain significance	Cardiomyopathy	2023-03-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000201450	SCV000914254	uncertain significance	Hypertrophic cardiomyopathy 1	2019-04-05	criteria provided, single submitter	clinical testing	The MYH7 c.4817G>A (p.Arg1606His) missense variant has been reported in two studies in which it is identified in a heterozygous state in at least five unrelated individuals with hypertrophic cardiomyopathy (Marsiglia et al. 2013; Walsh et al. 2017). Family history information was unavailable for the affected individuals. Control data are unavailable for this variant which is reported at a frequency of 0.000075 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg1606His variant is classified as a variant of uncertain significance but suspicious for pathogenicity for hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852453	SCV000995145	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2017-02-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769443	SCV001350551	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1606 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 individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 25031304, 27247418, 27532257, 28640247, 28771489, 29875424, 30297972, 33495597). This variant has been identified in 11/282872 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000766463	SCV004236714	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201450	SCV000256120	likely pathogenic	Hypertrophic cardiomyopathy 1		flagged submission	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035933	SCV000280355	uncertain significance	not specified	2013-04-04	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg1606His (c.4817 G>A) in the MYH7 gene. Based on the data reviewed below, we too classify this variant as of unknown clinical significance. The variant appears to be novel. As of November 2011, no variation at codon 1606 of MYH7 has been reported in the literature either in association with disease or as a benign polymorphism (according to searches of PubMed and Google). No variation at this codon is found in the following databases: NHLBI Exome Sequencing Project; dbSNP; 1000 Genomes; the Harvard Sarcomere Protein Gene Mutation Database; or UniProt. Furthermore, these databases report no missense variants within 10 amino acids to either side of this location. This variant has also not been seen in 200 Caucasian and African American presumably healthy controls tested at GeneDx. The Arginine at position 1606 is completely conserved across species. However, in silico analysis (PolyPhen-2) predicts the variant to be “benign.” This is a chemically conservative amino acid change. The variant substitutes one positively charged amino acid (Arg) with another positively charged amino acid (His).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766463	SCV001743689	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766463	SCV001969260	uncertain significance	not provided		no assertion criteria provided	clinical testing