ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.999C>T (p.Ser333=) (rs751646144)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617946 SCV000739451 likely benign Cardiovascular phenotype 2016-10-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign
GeneDx RCV000613652 SCV000725150 likely benign not specified 2017-11-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000460657 SCV000548932 uncertain significance Adams-Oliver syndrome 5 2016-10-18 criteria provided, single submitter clinical testing This sequence change affects codon 333 of the NOTCH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NOTCH1 protein. This variant is present in population databases (rs751646144, ExAC 0.009%) but has not been reported in the literature in individuals with a NOTCH1-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare silent change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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