ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1774C>A (p.Arg592Ser)

gnomAD frequency: 0.00011  dbSNP: rs764148985
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516565 SCV000614240 uncertain significance not provided 2019-09-24 criteria provided, single submitter clinical testing
GeneDx RCV000516565 SCV001987757 uncertain significance not provided 2019-05-24 criteria provided, single submitter clinical testing Reported previously as a variant of uncertain clinical significance in an individual with CADASIL, however familial segregation information was not included. (Ungaro et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28902129, 19006080)
Institute of Human Genetics, University Hospital Muenster RCV002287419 SCV002577795 uncertain significance See cases 2021-12-16 criteria provided, single submitter clinical testing ACMG categories: PM2,PM5,PP3,BP1
Invitae RCV000516565 SCV003491869 likely benign not provided 2023-11-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003409734 SCV004115205 uncertain significance NOTCH3-related condition 2022-11-04 criteria provided, single submitter clinical testing The NOTCH3 c.1774C>A variant is predicted to result in the amino acid substitution p.Arg592Ser. This variant was reported in an individual with white matter lesions; however no additional functional or familial segregation studies support its pathogenicity (Ungaro et al 2009. PubMed ID: 19006080). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-15297982-G-T). Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domains of the protein. This variant located in an extracellular EGFr-like domain, but does not involve a cysteine residue. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic RCV000516565 SCV004224584 uncertain significance not provided 2022-07-20 criteria provided, single submitter clinical testing BS2

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