ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1619A>G (p.Asp540Gly)

dbSNP: rs1568329461
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001213733 SCV001385382 likely pathogenic Pitt-Hopkins syndrome 2021-07-16 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of Pitt-Hopkins syndrome (Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces aspartic acid with glycine at codon 540 of the TCF4 protein (p.Asp540Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine.

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