ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3874C>T (p.His1292Tyr) (rs372348365)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466504 SCV000548927 uncertain significance Adams-Oliver syndrome 5 2016-06-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1292 of the NOTCH1 protein (p.His1292Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs372348365, ExAC 0.003%) but 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 output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The tyrosine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786381 SCV000925189 uncertain significance not provided 2016-08-09 no assertion criteria provided provider interpretation This variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign and tolerated (Polyphen and SIFT, respectively). The Histadine at codon 1292 is not well conserved across species and many other species also have a Tyr in that position. No other variants have been reported in association with this disease in clinvar in this region. There is one individual with variation at codon 1292 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~35,000 individuals of European, African, Latino and Asian descent (as of August 9, 2016). The average coverage at that site in ExAC is ~15x.

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