ClinVar Miner

Submissions for variant NM_001379200.1(TBX1):c.61G>A (p.Ala21Thr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV004555178 SCV005044107 likely pathogenic Velocardiofacial syndrome; DiGeorge syndrome 2022-02-11 criteria provided, single submitter clinical testing The inherited c.35-1G>A [NM_080647.1] splice-site variant identified has not been reported in affected individuals in the literature. The variant has 0.000006839 allele frequency in the gnomAD(v3) database [1 out of 146230 heterozygous alleles, no homozygote] suggesting it is not a common benign variant in populations represented in that database. The c.35-1G>A splice-site variant affects the canonical splice acceptor site in intron 2 (of 8) and is predicted to cause skipping of exon 3 of TBX1 gene. Exon 3 skipping is predicted to disrupt the wildtype translational reading frame and subject the transcript to nonsense-mediated mRNA decay. Loss-of-function variants in the TBX1 gene have been reported in affected individuals in the literature [PMID: 25860641, 29500247]. Depending on the mutation type and its localization, loss-of-function as well as dominant negative/gain-of-function effects have been proposed which may explain the extreme phenotypic variability among affected individuals [PMID: 25860641, 29500247, 17273972]. Based on the available evidence, the inherited c.35-1G>A splice-site variant identified is reported as Likely Pathogenic.

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