Submissions for variant NM_000192.3(TBX5):c.668C>T (p.Thr223Met) (rs1555225344)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre de Biologie Pathologie Génétique,Centre Hospitalier Universitaire de Lille	RCV000782334	SCV000920855	likely pathogenic	Holt-Oram syndrome	2018-06-14	no assertion criteria provided	clinical testing
GeneDx	RCV000519158	SCV000616887	pathogenic	not provided	2017-10-30	criteria provided, single submitter	clinical testing	The T223M variant has been published previously in association with Holt-Oram syndrome (Brassington et al., 2003; McDermott et al., 2005). The variant is not observed in large population cohorts (Lek et al., 2016). T223M is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that T223M interferes with the normal DNA-binding of the TBX5 protein (Stirnimann et al., 2010). In summary, we consider this variant to be pathogenic.
Invitae	RCV000654913	SCV000776817	pathogenic	Aortic valve disease 2	2017-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 223 of the TBX5 protein (p.Thr223Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with Holt-Oram Syndrome and has been shown to segregate with disease in affected families (PMID: 12789647, 16183809 ). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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