Submissions for variant NM_000192.3(TBX5):c.835C>T (p.Arg279Ter) (rs863223788)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre de Biologie Pathologie Génétique,Centre Hospitalier Universitaire de Lille	RCV000782289	SCV000920808	pathogenic	Holt-Oram syndrome	2018-06-14	no assertion criteria provided	clinical testing
GeneDx	RCV000196593	SCV000250830	pathogenic	not provided	2018-02-19	criteria provided, single submitter	clinical testing	The R279X nonsense variant in the TBX5 gene has been frequently reported in association with Holt-Oram syndrome (Heinritz et al., 2005; Brassington et al., 2003; Li et al., 1997). It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In vitro studies on cardiac tissue harboring R279X show significantly decreased TBX5 transcript levels compared to wild type (Baban et al., 2014).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000782289	SCV000992546	pathogenic	Holt-Oram syndrome	2019-03-20	criteria provided, single submitter	research
Invitae	RCV000459213	SCV000552104	pathogenic	Aortic valve disease 2	2018-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 279 (p.Arg279*) of the TBX5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBX5 are known to be pathogenic. This particular variant has been reported in the literature in several individuals affected with Holt-Oram syndrome (HOS) and Tetralogy of Fallot (TOF) (PMID: 21637475, 24664498, 25263169). ClinVar contains an entry for this variant (Variation ID: 213832). For these reasons, this variant has been classified as Pathogenic.