ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.7377G>A (p.Met2459Ile)

gnomAD frequency: 0.00003  dbSNP: rs139658777
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001878985 SCV002143855 uncertain significance Hajdu-Cheney syndrome 2024-09-29 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2459 of the NOTCH2 protein (p.Met2459Ile). This variant is present in population databases (rs139658777, gnomAD 0.009%). 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: 1371402). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NOTCH2 protein function with a negative predictive value of 95%. 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 RCV002478186 SCV002787441 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2024-04-19 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004741113 SCV005348638 uncertain significance NOTCH2-related disorder 2024-06-20 no assertion criteria provided clinical testing The NOTCH2 c.7377G>A variant is predicted to result in the amino acid substitution p.Met2459Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% 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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