ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.242C>G (p.Thr81Ser)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel RCV003098870 SCV005200080 uncertain significance Pitt-Hopkins syndrome 2024-06-25 reviewed by expert panel curation The highest population minor allele frequency of the p.Thr81Ser variant in TCF4 in gnomAD v4.1 is 0.000027 in the African population (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Thr81Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Thr81Ser variant in TCF4 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4).
Ambry Genetics RCV002450449 SCV002732917 likely benign Inborn genetic diseases 2019-10-15 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003098870 SCV003014376 uncertain significance Pitt-Hopkins syndrome 2022-10-04 criteria provided, single submitter clinical testing This variant is present in population databases (rs760934731, gnomAD 0.008%). 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 TCF4 protein function. This variant has not been reported in the literature in individuals affected with TCF4-related conditions. This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 81 of the TCF4 protein (p.Thr81Ser).

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