ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4700T>G (p.Phe1567Cys)

gnomAD frequency: 0.00001  dbSNP: rs750138024
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256739 SCV001433145 uncertain significance Hypertrophic cardiomyopathy 1 2020-02-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002327608 SCV002633950 uncertain significance Cardiovascular phenotype 2022-10-14 criteria provided, single submitter clinical testing The p.F1567C variant (also known as c.4700T>G), located in coding exon 31 of the MYH6 gene, results from a T to G substitution at nucleotide position 4700. The phenylalanine at codon 1567 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a dilated cardiomyopathy cohort; however, details were limited (Dal Ferro M et al. Heart, 2017 11;103:1704-1710). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003514494 SCV004296553 uncertain significance Hypertrophic cardiomyopathy 14 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1567 of the MYH6 protein (p.Phe1567Cys). This variant is present in population databases (rs750138024, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28416588). ClinVar contains an entry for this variant (Variation ID: 978298). 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.

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