ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1951C>G (p.Pro651Ala)

gnomAD frequency: 0.00001  dbSNP: rs549600113
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001351836 SCV001546338 uncertain significance Pitt-Hopkins syndrome 2020-03-17 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TCF4-related conditions. This variant is present in population databases (rs549600113, ExAC 0.01%). This sequence change replaces proline with alanine at codon 651 of the TCF4 protein (p.Pro651Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine.
Ambry Genetics RCV004681137 SCV005168178 likely benign Inborn genetic diseases 2024-03-20 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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