ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1554G>A (p.Thr518=)

gnomAD frequency: 0.00003  dbSNP: rs190721271
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001722638 SCV000717455 likely benign not provided 2020-10-15 criteria provided, single submitter clinical testing
Invitae RCV001070380 SCV001235606 uncertain significance Adams-Oliver syndrome 5 2023-02-27 criteria provided, single submitter clinical testing This sequence change affects codon 518 of the NOTCH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NOTCH1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs190721271, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 508333). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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 RCV002404633 SCV002704889 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-04-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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