ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.3406C>G (p.Gln1136Glu)

gnomAD frequency: 0.00001  dbSNP: rs1553195867
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001246620 SCV001419991 uncertain significance Hajdu-Cheney syndrome 2024-10-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1136 of the NOTCH2 protein (p.Gln1136Glu). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 970952). 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 80%. 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.
Johns Hopkins Genomics, Johns Hopkins University RCV002282499 SCV002570262 likely benign Alagille syndrome due to a NOTCH2 point mutation 2022-04-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV004960648 SCV005453408 likely benign Inborn genetic diseases 2024-07-02 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences RCV004740631 SCV005348500 uncertain significance NOTCH2-related disorder 2024-07-24 no assertion criteria provided clinical testing The NOTCH2 c.3406C>G variant is predicted to result in the amino acid substitution p.Gln1136Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% 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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