ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5017G>A (p.Gly1673Ser) (rs1226514285)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619894 SCV000739501 uncertain significance Cardiovascular phenotype 2017-09-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000533504 SCV000659453 uncertain significance Adams-Oliver syndrome 5 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1673 of the NOTCH1 protein (p.Gly1673Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. While this variant is not present in population databases, 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 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 C55"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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