Submissions for variant NM_001083962.2(TCF4):c.903C>T (p.Asn301=)

gnomAD frequency: 0.00003  dbSNP: rs781392344

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001125433	SCV005200079	benign	Pitt-Hopkins syndrome	2024-02-23	reviewed by expert panel	curation	The allele frequency of the p.Asn301= variant in TCF4 is 0.011% in East Asian sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Asn301= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Asn301= variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Asn301= variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Asn301= variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2, BP5).
Illumina Laboratory Services, Illumina	RCV001125433	SCV001284504	uncertain significance	Pitt-Hopkins syndrome	2018-04-20	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001712855	SCV001939070	likely benign	not provided	2020-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001125433	SCV002113919	likely benign	Pitt-Hopkins syndrome	2023-12-11	criteria provided, single submitter	clinical testing