ClinVar Miner

Submissions for variant NM_001032283.3(TMPO):c.565+1782G>A

dbSNP: rs763388598
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001293596 SCV001482213 likely benign not specified 2021-02-01 criteria provided, single submitter clinical testing Variant summary: TMPO c.1363G>A (p.Glu455Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251418 control chromosomes (gnomAD). The observed variant frequency is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in TMPO causing Dilated Cardiomyopathy phenotype (1.6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1363G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV002538425 SCV003243007 uncertain significance Loeys-Dietz syndrome 2 2022-06-23 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 997930). This variant has not been reported in the literature in individuals affected with TMPO-related conditions. This variant is present in population databases (rs763388598, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 455 of the TMPO protein (p.Glu455Lys).
Ambry Genetics RCV001293596 SCV003572210 likely benign not specified 2021-11-09 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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