ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1354G>A (p.Gly452Arg)

gnomAD frequency: 0.00002  dbSNP: rs138570124
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194093 SCV000249127 uncertain significance not specified 2015-05-29 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000725215 SCV000335039 uncertain significance not provided 2015-09-21 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000396501 SCV000409529 benign Pitt-Hopkins syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000396501 SCV001214213 uncertain significance Pitt-Hopkins syndrome 2023-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 452 of the TCF4 protein (p.Gly452Arg). This variant is present in population databases (rs138570124, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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: 212376). 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.

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