ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1250C>T (p.Ser417Leu) (rs757631575)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000655265 SCV000777195 uncertain significance Adams-Oliver syndrome 5 2017-08-22 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 417 of the NOTCH1 protein (p.Ser417Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs757631575, ExAC 0.009%). This variant has not been reported in the literature in individuals with 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: "Possibly Damaging"; 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001281020 SCV001468431 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2020-08-03 criteria provided, single submitter clinical testing NOTCH1 NM_017617.4 esxon 7 p.Ser417Leu (c.1250C>T): This variant has not been reported in the literature but is present in 0.008% (9/106554) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-139412594-G-A). This variant is present in ClinVar (Variation ID:544189). Evolutionary conservation suggests that this variant may not impact the protein, but computational predicitve tools predict a deleterious effect. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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