ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.2065C>A (p.Pro689Thr)

gnomAD frequency: 0.00003  dbSNP: rs748016197
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000476544 SCV000546169 uncertain significance Hypertrophic cardiomyopathy 14 2019-09-09 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 689 of the MYH6 protein (p.Pro689Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs748016197, ExAC 0.001%) but has not been reported in the literature in individuals with a MYH6-related disease. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002418370 SCV002724864 uncertain significance Cardiovascular phenotype 2024-11-17 criteria provided, single submitter clinical testing The p.P689T variant (also known as c.2065C>A), located in coding exon 16 of the MYH6 gene, results from a C to A substitution at nucleotide position 2065. The proline at codon 689 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics RCV002481416 SCV002784769 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-10-31 criteria provided, single submitter clinical testing

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