ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1625A>G (p.Lys542Arg)

gnomAD frequency: 0.00003  dbSNP: rs863224645
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199597 SCV000254442 pathogenic Hypertrophic cardiomyopathy 2022-08-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant disrupts the p.Lys542 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25547560). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216363). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22765922, 28356264). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 542 of the MYH7 protein (p.Lys542Arg).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755581 SCV000604368 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing The p.Lys542Arg variant (rs863224645) has been previously reported in two cohorts of cardiomyopathy patients (Coto 2012 and Walsh 2017); however, no additional clinical details or segregation data were provided. This variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 1 out of 30,928 chromosomes), and is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 216363). The lysine at codon 542 is highly conserved considering 12 species up to C. elegans (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on MYH7 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Additionally, a different variant affecting the same nucleotide (c.1625A>C; p.Lys542Thr) has been reported as a presumed de novo variant in a stillborn fetus with left ventricular noncompaction (LVNC; Nomura 2015) also suggesting importance of this amino acid. However, based on the available information, the clinical significance of the p.Lys542Arg variant cannot be determined with certainty.
GeneDx RCV000755581 SCV000617294 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing This variant has also been published in two individuals in association with HCM, though specific case-level data were not provided for these published cases (Coto et al., 2012; Walsh et al., 2017). The K542R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). 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. Nonetheless, the K542R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Ambry Genetics RCV002399746 SCV002708067 uncertain significance Cardiovascular phenotype 2020-11-30 criteria provided, single submitter clinical testing The p.K542R variant (also known as c.1625A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1625. The lysine at codon 542 is replaced by arginine, an amino acid with highly similar properties, and is located in the head domain. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts or cohorts referred for HCM genetic testing; however, clinical detail was limited (Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet Med, 2017 02;19:192-203). A different variant affecting this codon (p.K542T, c.1625A>C) has been reported in association with non-compaction cardiomyopathy (Nomura Y et al. Can J Cardiol, 2015 Jan;31:103.e1-3). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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