ClinVar Miner

Submissions for variant NM_001032283.3(TMPO):c.565+1390A>G

gnomAD frequency: 0.00001  dbSNP: rs780719278
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492839 SCV000582016 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMPO gene. The D324G variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 4/66,544 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D324G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp RCV001850639 SCV002115445 uncertain significance Loeys-Dietz syndrome 2 2022-11-08 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. 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 TMPO protein function. ClinVar contains an entry for this variant (Variation ID: 310766). This variant has not been reported in the literature in individuals affected with TMPO-related conditions. This variant is present in population databases (rs780719278, gnomAD 0.008%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 324 of the TMPO protein (p.Asp324Gly).
Ambry Genetics RCV004021557 SCV002693376 likely benign not specified 2022-07-06 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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