ClinVar Miner

Submissions for variant NM_017534.6(MYH2):c.1535C>T (p.Thr512Met)

gnomAD frequency: 0.00005  dbSNP: rs376478405
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000819364 SCV000960019 uncertain significance Myopathy, proximal, and ophthalmoplegia 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 512 of the MYH2 protein (p.Thr512Met). This variant is present in population databases (rs376478405, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 661850). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH2 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307628 SCV002600790 uncertain significance not specified 2022-10-28 criteria provided, single submitter clinical testing Variant summary: MYH2 c.1535C>T (p.Thr512Met) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1535C>T in individuals affected with Myopathy, Proximal, And Ophthalmoplegia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity RCV000819364 SCV003817201 uncertain significance Myopathy, proximal, and ophthalmoplegia 2019-12-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV004029005 SCV004945128 uncertain significance Inborn genetic diseases 2024-10-22 criteria provided, single submitter clinical testing The c.1535C>T (p.T512M) alteration is located in exon 15 (coding exon 13) of the MYH2 gene. This alteration results from a C to T substitution at nucleotide position 1535, causing the threonine (T) at amino acid position 512 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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