ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1727G>A (p.Arg576Gln)

dbSNP: rs1057521070
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Total submissions: 4
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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 RCV001507071 SCV001712044 pathogenic Pitt-Hopkins syndrome 2021-03-26 reviewed by expert panel curation The p.Arg576Gln variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Pitt-Hopkins syndrome (PMID 23033978, 28726809) (PS2_VS, PS4_supporting, PP4). The p.Arg576Gln variant in TCF4 is absent from gnomAD (PM2_supporting). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). The p.Arg576Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg576Gln variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2_VS, PM1, PS4_supporting, PM2_supporting, PP3, PP4).
GeneDx RCV000431775 SCV000520930 pathogenic not provided 2024-08-09 criteria provided, single submitter clinical testing Identified in a patient with Pitt-Hopkins syndrome in the literature who inherited the variant from a parent who is mosaic (PMID: 22045651); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24884844, 19235238, 24896178, 17436254, 18781613, 18728071, 28807867, 28726809, 23033978, 28191890, 12848929, 31785789, 33057194, 35982159, 22460224, 22045651)
Ambry Genetics RCV000623167 SCV000742334 pathogenic Inborn genetic diseases 2017-03-23 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003422397 SCV004117846 pathogenic TCF4-related disorder 2022-10-29 criteria provided, single submitter clinical testing The TCF4 c.1727G>A variant is predicted to result in the amino acid substitution p.Arg576Gln. This variant was reported to have occurred de novo in individuals with Pitt-Hopkins syndrome (Amiel et al. 2007. PubMed ID: 17436254; Table S3, de Ligt et al. 2012. PubMed ID: 23033978; reported as p.Arg412Gln in Table 2, Strauss et al. 2018. PubMed ID: 28726809). Functional studies suggested that this variant could impact protein function (Sepp et al. 2012. PubMed ID: 22460224). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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