ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.146G>A (p.Cys49Tyr)

dbSNP: rs193921045
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518559 SCV000614225 pathogenic not provided 2020-06-18 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant forms stable complexes with wild-type NOTCH3 resulting in slower clearance rate of proteins (PMID 23028706). Protein aggregation is considered to be the main pathogenic mechanism of the disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain
Invitae RCV000518559 SCV002286865 pathogenic not provided 2023-08-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys49 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17389000, 20935329). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects NOTCH3 function (PMID: 23028706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 447786). This missense change has been observed in individuals with CADASIL and/or clinical features of CADASIL (PMID: 9388399, 19174371, 19180562; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 49 of the NOTCH3 protein (p.Cys49Tyr).

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