ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1349T>C (p.Met450Thr)

gnomAD frequency: 0.00001  dbSNP: rs774283982
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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 RCV001057566 SCV005901543 uncertain significance Pitt-Hopkins syndrome 2025-02-28 reviewed by expert panel curation The highest population minor allele frequency of the p.Met450Thr variant in TCF4 in gnomAD v4.1.0 is 0.00001 in African/African American and European (Non-Finnish) populations (not sufficient to meet BS1 criteria). The p.Met450Thr variant is observed in at least 1 unaffected individual (internal data, LabCorp Genetics Inc.) (BS2_Supporting). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.523). In summary, the p.Met450Thr variant in TCF4 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2_Supporting). (TCF4 Specifications v3.0; curation approved on 02/28/2025).
Labcorp Genetics (formerly Invitae), Labcorp RCV001057566 SCV001222065 benign Pitt-Hopkins syndrome 2023-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002553836 SCV003552410 uncertain significance Inborn genetic diseases 2021-01-12 criteria provided, single submitter clinical testing The c.1349T>C (p.M450T) alteration is located in exon 15 (coding exon 14) of the TCF4 gene. This alteration results from a T to C substitution at nucleotide position 1349, causing the methionine (M) at amino acid position 450 to be replaced by a threonine (T). The in silico prediction for the p.M450T alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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