ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.1703G>A (p.Arg568His) (rs376291577)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819323 SCV000959977 uncertain significance Familial hypertrophic cardiomyopathy 14 2019-04-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 568 of the MYH6 protein (p.Arg568His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs376291577, ExAC 0.01%). This variant has not been reported in the literature in individuals with MYH6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002569 SCV001160542 uncertain significance not specified 2019-05-23 criteria provided, single submitter clinical testing The MYH6 c.1703G>A; p.Arg568His variant (rs376291577), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found in the general population with a low overall allele frequency of 0.004% (10/282832 alleles) in the Genome Aggregation Database. The arginine at codon 568 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another missense variant at the same residue (p.Arg568Cys) has been described in an individual with dilated cardiomyopathy (Hershberger 2010), although its clinical significance remains uncertain. Given the lack of clinical and functional data, the significance of the p.Arg568His variant is uncertain at this time. References: Hershberger RE et al. Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ Cardiovasc Genet. 2010 Apr;3(2):155-61.

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