ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.584A>G (p.Asn195Ser)

gnomAD frequency: 0.00001  dbSNP: rs148573556
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Total submissions: 3
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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 RCV001857661 SCV004035181 likely benign Pitt-Hopkins syndrome 2023-08-28 reviewed by expert panel curation The p.Asn195Ser variant in TCF4 is present in 3 female and 5 male individuals in gnomAD (0.005%) (not sufficient to meet BS1 criteria). The p.Asn195Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn195Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Asn195Ser variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Asn195Ser variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4, BP5).
GeneDx RCV001705057 SCV000243383 likely benign not provided 2021-06-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001857661 SCV002279265 uncertain significance Pitt-Hopkins syndrome 2023-10-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 195 of the TCF4 protein (p.Asn195Ser). This variant is present in population databases (rs148573556, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TCF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 207546). 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. 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.

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