ClinVar Miner

Submissions for variant NM_003238.6(TGFB2):c.346+1G>T

dbSNP: rs1553292145
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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 RCV001824364 SCV000826349 likely pathogenic Loeys-Dietz syndrome 4 2022-02-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the TGFB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TGFB2 are known to be pathogenic (PMID: 22772368, 22772371, 30739908). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 575492). Disruption of this splice site has been observed in individual(s) with TGFB2-related conditions (PMID: 30739908). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics RCV002458263 SCV002613033 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-05-19 criteria provided, single submitter clinical testing The c.346+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 1 of the TGFB2 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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