ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4210G>A (p.Val1404Met) (rs371552806)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035893 SCV000059544 uncertain significance not specified 2016-12-01 criteria provided, single submitter clinical testing The p.Val1404Met variant in MYH7 has been reported in 1 individual with HCM (Wan g 2014), and one with an unspecified mitochondrial disorder, but was also seen i n this individual's unaffected father (DaRe 2013). In addition, it has been iden tified by our laboratory in 1 Caucasian individual with DCM. This variant has be en identified in 2/66696 MYH7 chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs371552806). Computational predictio n tools and conservation analysis suggest that the p.Val1404Met variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Val1404Met variant i s uncertain.
GeneDx RCV000766458 SCV000208578 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing The V1404M variant has been published in association with HCM (Wang et al., 2014); however, additional clinical details and functional studies were not included. The V1404M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to valine are tolerated across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000198818 SCV000254447 uncertain significance Hypertrophic cardiomyopathy 2015-07-09 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1404 of the MYH7 protein (p.Val1404Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant has been reported in the literature in one individuals affected with hypertrophic cardiomyopathy (PMID: 25132132) and is present in population databases (rs371552806, 0.02%). Clinvar contains entries for this variant (RCV000158643, RCV000035893). 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 is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Color RCV000771884 SCV000904644 uncertain significance Cardiomyopathy 2019-07-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766458 SCV001149172 uncertain significance not provided 2017-04-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000771884 SCV001333663 uncertain significance Cardiomyopathy 2018-02-14 criteria provided, single submitter clinical testing

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