ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5519T>C (p.Met1840Thr) (rs149193520)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766470 SCV000279125 uncertain significance not provided 2018-12-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The M1840T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M1840T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The M1840T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to Methionine are tolerated across species. Missense variants in nearby residues (S1836L, R1845W) have been reported in the Human Gene Mutation Database in association with MYH7-related disorders (Stenson et al., 2014). Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
PreventionGenetics,PreventionGenetics RCV000214382 SCV000303250 likely benign not specified criteria provided, single submitter clinical testing
Invitae RCV000549508 SCV000623743 uncertain significance Hypertrophic cardiomyopathy 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1840 of the MYH7 protein (p.Met1840Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. The frequency data for this variant (rs149193520) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 234383). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000214382 SCV000917843 uncertain significance not specified 2018-09-10 criteria provided, single submitter clinical testing Variant summary: MYH7 c.5519T>C (p.Met1840Thr) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 275678 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5519T>C, has been reported in the literature in two individuals in one family affected with congenital heart defects, co-occurring with the pathogenic variant TBX5 c.709C>T (p.Arg237Trp) (Jia_2015). This report provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV001187338 SCV001354109 uncertain significance Cardiomyopathy 2019-09-17 criteria provided, single submitter clinical testing

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