Submissions for variant NM_001083962.2(TCF4):c.269A>G (p.Asn90Ser)

gnomAD frequency: 0.00067  dbSNP: rs143244149

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000332791	SCV001711968	benign	Pitt-Hopkins syndrome	2021-03-26	reviewed by expert panel	curation	The allele frequency of the p.Asn90Ser variant in TCF4 is 1.5% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Asn90Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn90Ser variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4).
Eurofins Ntd Llc (ga)	RCV000154003	SCV000203628	likely benign	not specified	2015-06-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000332791	SCV000409536	benign	Pitt-Hopkins syndrome	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000332791	SCV000646126	benign	Pitt-Hopkins syndrome	2024-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000154003	SCV000730146	benign	not specified	2017-05-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002316975	SCV000850494	benign	Inborn genetic diseases	2017-03-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000154003	SCV002067475	benign	not specified	2017-12-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003884365	SCV004700530	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TCF4: BS1