ClinVar Miner

Submissions for variant NM_080647.1(TBX1):c.684C>T (p.His228=) (rs200021644)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618363 SCV000736296 uncertain significance Cardiovascular phenotype 2016-09-01 criteria provided, single submitter clinical testing The c.684C>T variant (also known as p.H228H), located in coding exon 4 of the TBX1 gene, results from a C to T substitution at nucleotide position 684. This nucleotide substitution does not change the histidine at codon 228. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This variant was previously reported in the SNPDatabase as rs200021644. Based on data from ExAC, the T allele has an overall frequency of approximately 0.012% (13/105512). This nucleotide position is poorly conserved in available vertebrate species, and T is the reference nucleotide in numerous species. Using two different splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site by BDGP and strengthen the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001062273 SCV001227060 uncertain significance DiGeorge Syndrome 2019-12-15 criteria provided, single submitter clinical testing This sequence change affects codon 228 of the TBX1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TBX1 protein. This variant is present in population databases (rs200021644, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with TBX1-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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