ClinVar Miner

Submissions for variant NM_000192.3(TBX5):c.587C>A (p.Ser196Ter) (rs886041247)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000277503 SCV000329542 pathogenic not provided 2017-12-29 criteria provided, single submitter clinical testing The S196X nonsense variant in the TBX5 gene has been reported previously as an apparent de novo variant in a patient with Holt-Oram syndrome (Li et al., 1997); the variant was referred to as c.1493 C>A using alternate nomenclature. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider S196X to be a pathogenic variant.
Invitae RCV000654912 SCV000776816 pathogenic Aortic valve disease 2 2017-10-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser196*) in the TBX5 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Holt-Oran syndrome (PMID: 17534187, 15710732, 12789647, 10077612), including an individual where this variant arose de-novo ( PMID: 8988164) . This variant is also known as  c.1243C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 279906). Loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). For these reasons, this variant has been classified as Pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV000782331 SCV000920852 pathogenic Holt-Oram syndrome 2018-06-14 no assertion criteria provided clinical testing

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