Submissions for variant NM_181486.4(TBX5):c.787G>A (p.Val263Met)

gnomAD frequency: 0.00423  dbSNP: rs147405081

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180104	SCV000232478	likely benign	not specified	2018-05-21	criteria provided, single submitter	clinical testing
Invitae	RCV001087118	SCV000283867	benign	Aortic valve disease 2	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000299054	SCV000376502	likely benign	Holt-Oram syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000515032	SCV000610894	likely benign	not provided	2017-04-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620833	SCV000735178	benign	Cardiovascular phenotype	2015-10-01	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180104	SCV000920301	benign	not specified	2018-01-15	criteria provided, single submitter	clinical testing	Variant summary: The TBX5 c.787G>A (p.Val263Met) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Though a recent functional study demonstrated that the variant of interest could disrupts the TBX5-NuRD interaction (Waldron 2016), another study provided evidence that TBX5 activity may be extensively regulated through alternative splicing where the variant of interest would not affect isoforms lacking exon 9 (Yamak 2015). This variant was found in 403/276910 control chromosomes (with 1 homozygous occurrence), predominantly observed in the African subpopulation at a frequency of 0.012288 (295/24008). This frequency is about 2809 times the estimated maximal expected allele frequency of a pathogenic TBX5 variant (0.0000044), strong evidence that this is a benign polymorphism. The variant was reported in the literature in affected individuals, however without strong evidence for causality (Faria 2008, Bonachea 2014), i.e. no clear co-segregation could be demonstrated. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Mendelics	RCV000299054	SCV001138832	benign	Holt-Oram syndrome	2023-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000515032	SCV001845065	benign	not provided	2020-10-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18706711, 25260786)