ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3016C>T (p.Arg1006Cys)

dbSNP: rs1555727942
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517037 SCV000614269 pathogenic not provided 2023-05-10 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.3094C>T; p.Arg1006Cys. 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 variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
Invitae RCV000517037 SCV002228806 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1006 of the NOTCH3 protein (p.Arg1006Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 9388399, 15834039, 19576955, 23412372, 33020014). It has also been observed to segregate with disease in related individuals. This variant is also known as C3094T. ClinVar contains an entry for this variant (Variation ID: 447823). 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) has been performed at Invitae 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NOTCH3 function (PMID: 14714274). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000517037 SCV004565024 pathogenic not provided 2023-11-01 criteria provided, single submitter clinical testing The NOTCH3 c.3016C>T; p.Arg1006Cys variant (rs1555727942) is reported in the literature in several individuals affected with CADASIL (Cappelli 2009, Gonzalez 2020, Hu 2021, Joutel 1997, Ni 2022). This variant is also reported in ClinVar (Variation ID: 447823), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.569). However, most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus this variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Cappelli A et al. High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurosci Lett. 2009 Sep 22;462(2):176-8. PMID: 19576955. Gonzalez F et al. Non-convulsive status epilepticus as the initial manifestation in a family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologia (Engl Ed). 2020 Oct 2:S0213-4853(20)30214-0. English, Spanish. PMID: 33020014. Hu Y et al. NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Front Genet. 2021 Jul 15;12:705284. PMID: 34335700. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. PMID: 9388399. Ni W et al. Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. CNS Neurosci Ther. 2022 Nov;28(11):1779-1789. PMID: 35822697. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136.
GeneReviews RCV000845265 SCV000987227 not provided Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 no assertion provided literature only

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