Total submissions: 2
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. |
Prevention |
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. |