ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4817G>A (p.Arg1606His) (rs373514686)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035933 SCV000059584 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing The p.Arg1606His variant in MYH7 has been reported in 7 individuals with HCM (Ma rsiglia 2013, Helms 2014, Bos 2014, Lopes 2015, LMM data), one of whom carried a pathogenic variant in MYH7 that was sufficient to cause their disease (LMM data ). This variant has also been reported in ClinVar (Variation ID 43039) and in 9/ 126718 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs373514686). Computational prediction tools and conservation analysis suggest that the p.Arg1606His variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, the clinical significance of the p.Arg1606His variant is uncertain .
GeneDx RCV000766463 SCV000208607 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing The R1606H variant of uncertain significance in the MYH7 gene has been published in one Brazilian individual with HCM (Marsiglia et al., 2013), and in other individuals referred for cardiomyopathy genetic testing whose personal clinical history was not specified (Homburger et al., 2016; Walsh et al., 2017). This variant has also been identified independently and in conjunction with additional cardiogenetic variants in individuals referred for HCM genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The R1606H variant has been observed in 9/126,718 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the R1606H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. And while a missense variant in the same residue (R1606C), as well as missense variants in nearby residues (R1608P, E1610Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of each of these variants has not been definitively determined.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201450 SCV000256120 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000475488 SCV000546266 uncertain significance Hypertrophic cardiomyopathy 2018-02-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1606 of the MYH7 protein (p.Arg1606His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs373514686, ExAC 0.009%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 25031304, 27247418, 27532257, 28771489). ClinVar contains an entry for this variant (Variation ID: 43039). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619414 SCV000739973 uncertain significance Cardiovascular phenotype 2016-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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 2017-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000201450 SCV000914254 uncertain significance Familial 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
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).

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