ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.3652C>T (p.Arg1218Trp)

gnomAD frequency: 0.00003  dbSNP: rs587641573
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638605 SCV000760142 uncertain significance Hajdu-Cheney syndrome 2020-06-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1218 of the NOTCH2 protein (p.Arg1218Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs587641573, ExAC 0.01%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NOTCH2-related disease.
PreventionGenetics, part of Exact Sciences RCV003420116 SCV004109417 uncertain significance NOTCH2-related condition 2022-11-23 criteria provided, single submitter clinical testing The NOTCH2 c.3652C>T variant is predicted to result in the amino acid substitution p.Arg1218Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120478098-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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