ClinVar Miner

Submissions for variant NM_000192.3(TBX5):c.710G>A (p.Arg237Gln) (rs104894378)

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Total submissions: 5
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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 RCV000008457 SCV000920860 pathogenic Holt-Oram syndrome 2018-06-14 no assertion criteria provided clinical testing
GeneDx RCV000196777 SCV000250816 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing The R237Q missense variant in the TBX5 gene has been reported previously in association with Holt-Oram syndrome (Basson et al., 1999). The variant is observed in 1/8726 (0.012%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The R237Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In vitro functional studies demonstrated that the presence of the variant results in reduced DNA-binding activity, reduced transcriptional activation, and failure to act with transcriptional activation in comparison to wild-type (Fan et al., 2003). Missense variants in the same residue (R237W/P) have been reported in the Human Gene Mutation Database in association with Holt-Oram syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Invitae RCV000474989 SCV000552109 pathogenic Aortic valve disease 2 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 237 of the TBX5 protein (p.Arg237Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two families affected with Holt-Oram syndrome (PMID: 8988165, 12789647). ClinVar contains an entry for this variant (Variation ID: 7993). This missense change is located in the T-box domain of TBX5, and has been shown in experimental studies to affect TBX5 DNA binding and interaction with NKX2-5 and GATA4, resulting in reduced activation of downstream targets (PMID: 11555635, 12499378). Two additional missense substitutions at this codon (p.Arg237Trp and p.Arg237Pro) have been reported to be deleterious (PMID: 10077612, 12499378, 12789647, 20519243). This suggests that the arginine residue is critical for TBX5 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000008457 SCV000205351 likely pathogenic Holt-Oram syndrome 2013-04-12 criteria provided, single submitter clinical testing The Arg237Gln variant in TBX5 has been reported in two individuals with Holt-Ora m syndrome and segregated with disease in one affected relative (Basson 1997, Ba sson 1999). This variant has not been identified in large population studies, bu t is listed in dbSNP without frequency information (rs104894378). The TBX5 gene encodes a transcription factor and the variant is located in the DNA binding dom ain and functional studies indicate that it affects protein function (Ghosh 2001 , Hiroi 2001, Fan 2003, Fan 2009, Stirnimann 2010, Wang 2011). Computational ana lyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, an d SIFT) also support that this variant may impact the protein as does the presen ce of other variants at this position that have been detected in individuals wit h Holt Oram syndrome (Arg237Pro, Arg237Trp; Basson 1999, Boogerd 2010). In summa ry, the Arg237Gln variant is likely pathogenic, though additional studies are re quired to fully establish its clinical significance.
OMIM RCV000008457 SCV000028665 pathogenic Holt-Oram syndrome 1999-03-16 no assertion criteria provided literature only

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