ClinVar Miner

Submissions for variant NM_001032283.3(TMPO):c.565+1328G>T

gnomAD frequency: 0.00006  dbSNP: rs369208265
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Total submissions: 4
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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 RCV000152054 SCV000200665 uncertain significance not specified 2014-12-18 criteria provided, single submitter clinical testing The p.Met303Ile variant in TMPO has been identified by our laboratory in 1 indiv idual with ischemic cardiomyopathy. This variant has also been identified in 2/6 7574 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs369208265). Methionine (Met) at position 303 is not conserved in mammals or evolutionarily distant species and 1 mammal (squirrel m onkey) carries an isoleucine (Ile) at this position, raising the possibility tha t this change may be tolerated. Additional computational prediction tools also s uggest that the p.Met303Ile variant may not impact the protein, though this info rmation is not predictive enough to rule out pathogenicity. In summary, the clin ical significance of the p.Met303Ile variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000815161 SCV000955608 uncertain significance Loeys-Dietz syndrome 2 2023-11-06 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 303 of the TMPO protein (p.Met303Ile). This variant is present in population databases (rs369208265, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TMPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 165468). 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 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.
Ambry Genetics RCV000152054 SCV003911810 uncertain significance not specified 2024-08-01 criteria provided, single submitter clinical testing The c.909G>T (p.M303I) alteration is located in exon 4 (coding exon 4) of the TMPO gene. This alteration results from a G to T substitution at nucleotide position 909, causing the methionine (M) at amino acid position 303 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV003227675 SCV003924992 uncertain significance not provided 2022-11-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with cardiomyopathy or other TMPO-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 28404951)

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