ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.649A>T (p.Met217Leu)

gnomAD frequency: 0.00001  dbSNP: rs768573052
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002318309 SCV000851663 uncertain significance Inborn genetic diseases 2017-04-20 criteria provided, single submitter clinical testing The p.M217L variant (also known as c.649A>T), located in coding exon 8 of the TCF4 gene, results from an A to T substitution at nucleotide position 649. The methionine at codon 217 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001237542 SCV001410305 uncertain significance Pitt-Hopkins syndrome 2023-09-10 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with TCF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 590129). 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 TCF4 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. This variant is present in population databases (rs768573052, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 217 of the TCF4 protein (p.Met217Leu).
GeneDx RCV001759439 SCV001985284 uncertain significance not provided 2019-04-23 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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