ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.743G>C (p.Gly248Ala)

gnomAD frequency: 0.00005  dbSNP: rs141402160
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000991727 SCV001143408 uncertain significance not provided 2019-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000991727 SCV005333616 uncertain significance not provided 2024-03-15 criteria provided, single submitter clinical testing Identified with a second NOTCH3 variant in two cousins with Alzheimer Disease, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 30924900); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34151536, 30924900)
Labcorp Genetics (formerly Invitae), Labcorp RCV000991727 SCV005830104 uncertain significance not provided 2024-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 248 of the NOTCH3 protein (p.Gly248Ala). This variant is present in population databases (rs141402160, gnomAD 0.009%). This missense change has been observed in individual(s) with Alzheimer disease (PMID: 30924900). ClinVar contains an entry for this variant (Variation ID: 804652). 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 NOTCH3 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.

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