ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.839T>C (p.Met280Thr)

dbSNP: rs1568580200
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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 RCV000692498 SCV000820324 uncertain significance Pitt-Hopkins syndrome 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 280 of the TCF4 protein (p.Met280Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TCF4-related disease.
GeneDx RCV001766486 SCV001998731 uncertain significance not provided 2020-01-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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