ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.633C>G (p.Phe211Leu)

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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 RCV003778317 SCV004617203 uncertain significance Pitt-Hopkins syndrome 2023-08-02 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. Experimental studies have shown that this missense change does not substantially affect TCF4 function (PMID: 34748727). 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 variant is present in population databases (rs776969005, gnomAD 0.004%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the TCF4 protein (p.Phe211Leu).
PreventionGenetics, part of Exact Sciences RCV003419256 SCV004115273 uncertain significance TCF4-related disorder 2024-02-24 no assertion criteria provided clinical testing The TCF4 c.633C>G variant is predicted to result in the amino acid substitution p.Phe211Leu. To our knowledge, this variant has not been reported in the literature. A different nucleotide substitution resulting in the same missense variant p.Phe211Leu was observed in a patient with schizophrenia (Basmanav et al. 2015. PubMed ID: 26010163). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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