ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.245G>T (p.Cys82Phe)

dbSNP: rs1023306013
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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 Inc RCV000516733 SCV000614257 pathogenic not provided 2021-03-08 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. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic mutations associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000516733 SCV001158232 likely pathogenic not provided 2019-08-27 criteria provided, single submitter clinical testing The NOTCH3 c.245G>T; p.Cys82Phe variant (rs1023306013), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 447812). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 82 occurs within an EGF domain and is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. The vast majority of causative missense variants identified in individuals with CADASIL either create or remove EGF domain cysteine residues, as these are involved in the formation of disulfide bridges critical to protein folding (Dichgans 2000, Joutel 1997). Based on available information, this variant is considered to be likely pathogenic. References: Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5.
Invitae RCV000516733 SCV002118641 pathogenic not provided 2021-11-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 82 of the NOTCH3 protein (p.Cys82Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy and lateral meningocele syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 447812). 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. This variant disrupts the p.Cys82 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25096610). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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