ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.7363A>G (p.Thr2455Ala) (rs536167222)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250238 SCV000320233 uncertain significance Cardiovascular phenotype 2015-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Fulgent Genetics,Fulgent Genetics RCV000766053 SCV000897509 uncertain significance Aortic valve disorder; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000816086 SCV000956576 uncertain significance Adams-Oliver syndrome 5 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 2455 of the NOTCH1 protein (p.Thr2455Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs536167222, ExAC 0.007%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 264349). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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