ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.2785G>A (p.Gly929Arg)

gnomAD frequency: 0.00009  dbSNP: rs199585130
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001316334 SCV001506950 uncertain significance Hajdu-Cheney syndrome 2023-08-08 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 929 of the NOTCH2 protein (p.Gly929Arg). This variant is present in population databases (rs199585130, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NOTCH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1017215). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH2 protein function. 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.
Fulgent Genetics, Fulgent Genetics RCV002476472 SCV002790178 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2021-12-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003399093 SCV004106094 uncertain significance NOTCH2-related disorder 2022-12-22 criteria provided, single submitter clinical testing The NOTCH2 c.2785G>A variant is predicted to result in the amino acid substitution p.Gly929Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120484345-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics RCV004034391 SCV004990190 uncertain significance Inborn genetic diseases 2024-01-30 criteria provided, single submitter clinical testing The c.2785G>A (p.G929R) alteration is located in exon 18 (coding exon 18) of the NOTCH2 gene. This alteration results from a G to A substitution at nucleotide position 2785, causing the glycine (G) at amino acid position 929 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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