ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.421G>A (p.Ala141Thr)

gnomAD frequency: 0.00009  dbSNP: rs776853139
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000172036 SCV000054820 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001327220 SCV001518283 uncertain significance Hypertrophic cardiomyopathy 14 2023-04-18 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 191722). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). This variant is present in population databases (rs776853139, gnomAD 0.005%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 141 of the MYH6 protein (p.Ala141Thr).
GeneDx RCV000172036 SCV001986806 uncertain significance not provided 2020-10-20 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221)
Ambry Genetics RCV002326946 SCV002629530 uncertain significance Cardiovascular phenotype 2023-12-07 criteria provided, single submitter clinical testing The p.A141T variant (also known as c.421G>A), located in coding exon 3 of the MYH6 gene, results from a G to A substitution at nucleotide position 421. The alanine at codon 141 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort and was also noted in a healthy control (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This alteration has also been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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