ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.2501T>G (p.Leu834Trp)

gnomAD frequency: 0.00002  dbSNP: rs376526633
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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 RCV001989871 SCV002236037 uncertain significance Hajdu-Cheney syndrome 2024-10-17 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 834 of the NOTCH2 protein (p.Leu834Trp). This variant is present in population databases (rs376526633, gnomAD 0.004%). 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: 1449908). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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 RCV002484783 SCV002790712 likely benign Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2024-05-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV005374947 SCV006039576 likely benign Inborn genetic diseases 2025-02-25 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.

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