ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.6878A>C (p.His2293Pro)

gnomAD frequency: 0.00002  dbSNP: rs780904023
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001950467 SCV002218749 uncertain significance Hajdu-Cheney syndrome 2023-08-29 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1440665). 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. 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. This variant has not been reported in the literature in individuals affected with NOTCH2-related conditions. This variant is present in population databases (rs780904023, gnomAD 0.01%). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2293 of the NOTCH2 protein (p.His2293Pro).
Fulgent Genetics, Fulgent Genetics RCV002497818 SCV002806771 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2021-12-23 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003913463 SCV004735387 uncertain significance NOTCH2-related disorder 2024-02-19 criteria provided, single submitter clinical testing The NOTCH2 c.6878A>C variant is predicted to result in the amino acid substitution p.His2293Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. 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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