Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000007795 | SCV001712047 | pathogenic | Pitt-Hopkins syndrome | 2021-03-26 | reviewed by expert panel | curation | The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4). |
Gene |
RCV000387138 | SCV000329544 | pathogenic | not provided | 2023-03-17 | criteria provided, single submitter | clinical testing | In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., 2012; Forrest et al,. 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22460224, 29318938, 22777675, 17436254, 18781613, 26621827, 17436255, 16531728, 29655203, 31130284, 32369273, 33624935, 31785789, 35599849, 35719373) |
Molecular Genetics Laboratory, |
RCV000007795 | SCV000898160 | pathogenic | Pitt-Hopkins syndrome | 2018-08-30 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
RCV000387138 | SCV001430911 | pathogenic | not provided | 2020-07-28 | criteria provided, single submitter | clinical testing | PS2, PS3, PS4, PM2 |
National Institute of Neuroscience, |
RCV000007795 | SCV001438319 | pathogenic | Pitt-Hopkins syndrome | criteria provided, single submitter | research | ||
Ambry Genetics | RCV001266245 | SCV001444417 | pathogenic | Inborn genetic diseases | 2019-10-02 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000387138 | SCV001447787 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000007795 | SCV001586248 | pathogenic | Pitt-Hopkins syndrome | 2023-07-25 | criteria provided, single submitter | clinical testing | 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 expected to disrupt TCF4 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg580 amino acid residue in TCF4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17436254, 19235238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TCF4 function (PMID: 22460224, 22777675). ClinVar contains an entry for this variant (Variation ID: 7370). This variant is also known as c.1726C>T; p.R576W. This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PHS) (PMID: 17436254, 17436255). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 580 of the TCF4 protein (p.Arg580Trp). |
Suma Genomics | RCV000007795 | SCV001653506 | pathogenic | Pitt-Hopkins syndrome | criteria provided, single submitter | clinical testing | ||
Institute of Human Genetics, |
RCV000007795 | SCV002576439 | pathogenic | Pitt-Hopkins syndrome | 2022-08-29 | criteria provided, single submitter | clinical testing | This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM5, PS3_SUP, PM2_SUP, PP3 |
OMIM | RCV000007795 | SCV000027996 | pathogenic | Pitt-Hopkins syndrome | 2007-05-01 | no assertion criteria provided | literature only | |
Laboratory of Molecular Genetics, |
RCV000415008 | SCV000493081 | likely pathogenic | Severe intellectual deficiency | no assertion criteria provided | clinical testing |