ClinVar Miner

Submissions for variant NM_001145809.2(MYH14):c.1265C>G (p.Ala422Gly)

gnomAD frequency: 0.00005  dbSNP: rs372324948
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000151184 SCV000199009 uncertain significance not specified 2013-06-28 criteria provided, single submitter clinical testing The Ala422Gly variant in MYH14 has not been reported in individuals with hearing loss but has been identified in 0.02% (2/8498) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Alth ough this variant was identified in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not prov ide strong support for or against an impact to the protein. In summary, additio nal data is needed to determine the clinical significance of this variant.
Invitae RCV002516034 SCV003501079 uncertain significance not provided 2023-11-19 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 414 of the MYH14 protein (p.Ala414Gly). This variant is present in population databases (rs372324948, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 164172). 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 MYH14 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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