ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.865+2C>T

dbSNP: rs1164392989
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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 RCV001864462 SCV002129858 uncertain significance Adams-Oliver syndrome 5 2024-10-17 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the NOTCH1 gene. It does not directly change the encoded amino acid sequence of the NOTCH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1371166). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Ambry Genetics RCV002370415 SCV002685643 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-12-26 criteria provided, single submitter clinical testing The c.865+2C>T intronic variant results from a C to T substitution two nucleotides after coding exon 5 in the NOTCH1 gene. 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. However, this nucleotide position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice donor site; however, direct evidence is unavailable. An alternate nucleotide substitution at this position with predicted splicing impact, c.865+2C>A, was reported in affected individuals from a family with bicuspid aortic valve, thoracic aortic aneurysm, and congenital heart defects (Kerstjens-Frederikse WS et al. Genet. Med., 2016 09;18:914-23). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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