ClinVar Miner

Submissions for variant NM_181486.4(TBX5):c.756-2A>G

dbSNP: rs1869545659
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001229255 SCV001401695 likely pathogenic Aortic valve disease 2 2019-11-04 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of Holt-Oram syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the TBX5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Illumina Laboratory Services, Illumina RCV001270727 SCV001451474 pathogenic Holt-Oram syndrome 2019-04-15 criteria provided, single submitter clinical testing The TBX5 c.756-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the potential impact of splice acceptor site variants, its rarity and application of the ACMG criteria, the c.756-2A>G variant is classified as pathogenic for Holt-Oram syndrome.

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