ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.775G>A (p.Asp259Asn) (rs763187824)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253079 SCV000319684 uncertain significance Cardiovascular phenotype 2015-05-22 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
GeneDx RCV000523362 SCV000620987 uncertain significance not provided 2017-09-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The D259N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D259N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across most species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Fulgent Genetics,Fulgent Genetics RCV000764822 SCV000895973 uncertain significance Aortic valve disorder; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001054792 SCV001219143 uncertain significance Adams-Oliver syndrome 5 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 259 of the NOTCH1 protein (p.Asp259Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs763187824, ExAC 0.009%). This variant has not been reported in the literature in individuals with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 264044). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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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