ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4988G>A (p.Arg1663Gln) (rs749490844)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557460 SCV000659452 uncertain significance Adams-Oliver syndrome 5 2017-01-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1663 of the NOTCH1 protein (p.Arg1663Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. While this variant is present in population databases (rs749490844), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620626 SCV000739404 uncertain significance Cardiovascular phenotype 2019-10-01 criteria provided, single submitter clinical testing The p.R1663Q variant (also known as c.4988G>A), located in coding exon 26 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 4988. The arginine at codon 1663 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000766056 SCV000897512 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV001553148 SCV001773964 uncertain significance not provided 2020-12-15 criteria provided, single submitter clinical testing Has not been definitively reported in the germline as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 477936; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31866570)

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