ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs373514686
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Total submissions: 14
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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 ( 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 c.4817G>A (p.R1606H) alteration is located in exon 34 (coding exon 32) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 4817, causing the arginine (R) at amino acid position 1606 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, 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

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