ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.5542C>T (p.Arg1848Cys)

gnomAD frequency: 0.00001  dbSNP: rs570853853
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618134 SCV000736708 uncertain significance Cardiovascular phenotype 2016-11-05 criteria provided, single submitter clinical testing The p.R1848C variant (also known as c.5542C>T), located in coding exon 34 of the MYH6 gene, results from a C to T substitution at nucleotide position 5542. The arginine at codon 1848 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was previously reported in the SNPDatabase as rs570853853. Based on data from ExAC, the T allele has an overall frequency of <0.01% (2/106104). This amino acid position is highly conserved in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000807126 SCV000947165 uncertain significance Hypertrophic cardiomyopathy 14 2021-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1848 of the MYH6 protein (p.Arg1848Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs570853853, ExAC 0.01%). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 518955). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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