rs137852642
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000435.3(NOTCH3):c.397C>T(p.Arg133Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000435.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000451 AC: 1AN: 221490Hom.: 0 AF XY: 0.00000829 AC XY: 1AN XY: 120636
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1450026Hom.: 0 Cov.: 39 AF XY: 0.00000278 AC XY: 2AN XY: 720456
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:8Other:2
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Variant interpreted as Pathogenic and most recently reported on 09-17-2018 by Lab or GTR ID 1012. Variant also interpreted as Pathogenic and reported on 05-12-2019 by GTR ID 500035. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -
PM1, PM2, PP2, PP3, PP5 -
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The observed missense c.397C>T(p.Arg133Cys) in NOTCH3 gene has been reported in heterozygous state in individuals affected with CADSIL (Li J, et. al.,2022; Mönkäre S, et. al., 2022).Experimental studies suggests that the variant causes protein aggregation and ER retention, resulting in impaired cell proliferation (Schoemaker D, et. al., 2021). This variant is present with an allele frequency of 0.0004% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Likely pathogenic/Pathogenic (multiple submission). The amino acid change p.Arg133Cys in NOTCH3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 133 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT -probably Damaging, and MutationTaster - disease causing automatic) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP2,PP3. -
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Variant summary: NOTCH3 c.397C>T (p.Arg133Cys) results in a non-conservative amino acid change located in the EGF like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-06 in 221490 control chromosomes. c.397C>T has been reported in the literature in multiple individuals affected with Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (example: Mukai_2020). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 32277177). ClinVar contains an entry for this variant (Variation ID: 9225). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:6
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in at least one individual with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant causes protein aggregation and ER retention, resulting in impaired cell proliferation (PMID: 19825845). 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. -
PP3, PP4, PP5, PM1, PS3, PS4 -
The NOTCH3 c.397C>T; p.Arg133Cys variant (rs137852642) has been described in multiple individuals affected with CADASIL (Joutel 1997, Maclean 2005, Mykkanen 2004). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 9225), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 133 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In vitro characterization of this variant protein demonstrates increased spontaneous multimerization compared to wild-type (Opherk 2009). Based on available information, this variant is considered to be pathogenic. References: Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Maclean A et al. Spontaneous lobar haemorrhage in CADASIL. J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):456-7. Mykkanen K et al. Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet. 2004 Oct;12(10):813-9. Opherk C et al. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet. 2009 Aug 1;18(15):2761-7. -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 133 of the NOTCH3 protein (p.Arg133Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CADASIL (PMID: 10969905, 22019870, 28334938). ClinVar contains an entry for this variant (Variation ID: 9225). 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) indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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Published functional studies suggest that the R133C impacts protein function (Opherk et al., 2009; Takahashi et al., 2010; Wollenweber et al., 2015); 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: 10854111, 26261665, 11771160, 25819272, 15378071, 15364702, 16009764, 9388399, 15350543, 19417009, 19825845, 10969905, 11715067, 15716553, 22623959, 22019870, 11486103, 25604251, 28334938, 28534048, 10371548, 12810003, 11755616, 31571467, 31554780, 30402942, 31720972, 34335700, 34008892, 15143298, 10609671, 36047879, 32555735, 34741685, 10766655, 30392756, 16877080, 32277177, 24844136) -
Recurrent subcortical infarcts Pathogenic:1
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NOTCH3-related disorder Pathogenic:1
The NOTCH3 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Cys. This variant has been reported as causative for CADASIL in numerous affected individuals and its pathogenicity is supported by functional studies (Joutel et al. 1997. PubMed ID: 9388399; Wollenweber et al. 2015. PubMed ID: 25604251). Of note, the vast majority of CADASIL-causing variants in the NOTCH3 gene are predicted to result in the gain or loss of cysteine residues in the extracellular domain of the protein, as seen in this patient. At PreventionGenetics, we have previously detected this variant in other affected individuals. This variant is reported in 0.0052% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic/likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9225/). This variant is interpreted as pathogenic. -
Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:1
Criteria Codes: PS3_Str PS4_Mod PM1_Str PP1_Str PP2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at