ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.5111C>T (p.Ala1704Val)

gnomAD frequency: 0.00002  dbSNP: rs776961989
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626823 SCV000747526 uncertain significance Hypertrophic cardiomyopathy; Chest pain 2017-01-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000688297 SCV000815902 uncertain significance Hypertrophic cardiomyopathy 14 2022-07-25 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with cardiomyopathy (PMID: 27600940). 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 523452). This variant is present in population databases (rs776961989, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1704 of the MYH6 protein (p.Ala1704Val).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201319 SCV001372463 uncertain significance not specified 2020-06-29 criteria provided, single submitter clinical testing Variant summary: MYH6 c.5111C>T (p.Ala1704Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250820 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5111C>T has been reported in the literature in individuals affected with HCM (Cecconi_2016). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV004639290 SCV005143020 uncertain significance Cardiovascular phenotype 2024-06-10 criteria provided, single submitter clinical testing The p.A1704V variant (also known as c.5111C>T), located in coding exon 32 of the MYH6 gene, results from a C to T substitution at nucleotide position 5111. The alanine at codon 1704 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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