ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4231G>A (p.Ala1411Thr)

gnomAD frequency: 0.00002  dbSNP: rs146172839
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University RCV003319262 SCV003932398 uncertain significance Primary dilated cardiomyopathy 2023-06-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003629258 SCV004425979 uncertain significance Hypertrophic cardiomyopathy 14 2024-02-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1411 of the MYH6 protein (p.Ala1411Thr). This variant is present in population databases (rs146172839, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and congenital heart defect (PMID: 33658040, 35993536). ClinVar contains an entry for this variant (Variation ID: 2505329). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV005377351 SCV006034006 uncertain significance Cardiovascular phenotype 2025-02-28 criteria provided, single submitter clinical testing The p.A1411T variant (also known as c.4231G>A), located in coding exon 28 of the MYH6 gene, results from a G to A substitution at nucleotide position 4231. The alanine at codon 1411 is replaced by threonine, an amino acid with similar properties. This variant has been reported in a hypertrophic cardiomyopathy (HCM) cohort, a pediatric cardiomyopathy cohort and a congenital heart disease cohort (Chung H et al. J Cardiovasc Magn Reson, 2021 Mar;23:18; Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298; Zhang Y et al. Mol Genet Genomic Med, 2022 Oct;10:e2041). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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