ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4850A>C (p.Lys1617Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002340289 SCV002639367 uncertain significance Cardiovascular phenotype 2021-10-02 criteria provided, single submitter clinical testing The p.K1617T variant (also known as c.4850A>C), located in coding exon 31 of the MYH6 gene, results from an A to C substitution at nucleotide position 4850. The lysine at codon 1617 is replaced by threonine, an amino acid with similar properties. This variant has been reported in cases from a cohort with left ventricular noncompaction and hypertrabeculation (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003096495 SCV003520096 uncertain significance Hypertrophic cardiomyopathy 14 2024-08-06 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1617 of the MYH6 protein (p.Lys1617Thr). This variant is present in population databases (rs141375292, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 28798025, 35893073). ClinVar contains an entry for this variant (Variation ID: 1743580). 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 expected to disrupt MYH6 protein function with a positive 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.

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