rs75068032
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong
The NM_000435.3(NOTCH3):c.1672C>T(p.Arg558Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,970 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 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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NOTCH3 | ENST00000263388.7 | c.1672C>T | p.Arg558Cys | missense_variant | Exon 11 of 33 | 1 | NM_000435.3 | ENSP00000263388.1 | ||
NOTCH3 | ENST00000601011.1 | c.1669C>T | p.Arg557Cys | missense_variant | Exon 11 of 23 | 5 | ENSP00000473138.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251034Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135824
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461746Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727188
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74368
ClinVar
Submissions by phenotype
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:6
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It is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.003%. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447794). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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Variant summary: NOTCH3 c.1672C>T (p.Arg558Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 251034 control chromosomes. c.1672C>T has been reported in the literature in multiple individuals affected with Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Ilinca_2020, Craggs_2013, Peters_2005, Joutel_1996). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32172663, 23844775, 16009764, 8878478). ClinVar contains an entry for this variant (Variation ID: 447794). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:4
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 is statistically more frequent in individuals with CADASIL than in the general population and/or healthy controls. This variant occurs as the most likely explanation for disease in a significant number of 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 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). -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 558 of the NOTCH3 protein (p.Arg558Cys). This variant is present in population databases (rs75068032, gnomAD 0.005%). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 8878478, 16009764, 23844775, 32172663). This variant is also known as CGC>TGC; R>C in N12. ClinVar contains an entry for this variant (Variation ID: 447794). 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. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8878478, 29757481, 9388399, 11102981, 15364702, 16009764, 24086431, 19174371, 27844030, 23844775, 11755616, 22218279, 25929831, 28710804, 31028544, 33130454, 32172663, 29188608, 31589614, 34851492, Cebi2021[Article], Rustemoglu2021[article], 37152446, 34741685, 24844136, 36380532, 36261288, 36047879, 36411388, 35130036, 35523050, 25344745, 17122431, 33535780, 26646783, 38162905, 31146726) -
The NOTCH3 c.1672C>T; p.Arg558Cys variant (rs75068032) is reported in the literature in individuals affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Anamnart 2019, Capalbo 2019, Craggs 2014, Fernandez 2015, Joutel 1997, Hu 2022). This variant is only observed on nine alleles in the Genome Aggregation Database (9/282416 alleles), indicating it is not a common polymorphism. The arginine at codon 558 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.672). However, this variant creates a cysteine in an EGF-like domain and most pathogenic NOTCH3 variants create or destroy a cysteine residue within an EGF-like domain (Rutten 2014); thus, the p.Arg558Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Anamnart C et al. A large number of cerebral microbleeds in CADASIL patients presenting with recurrent seizures: a case report. BMC Neurol. 2019 May 30;19(1):106. PMID: 31146726 Capalbo A et al. Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. PLoS Genet. 2019 Oct 7;15(10):e1008409. PMID: 31589614 Craggs LJ et al. White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neuropathol Appl Neurobiol. 2014 Aug;40(5):591-602. PMID: 23844775 Fernández A et al. A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients. J Mol Neurosci. 2015 Jul;56(3):613-6. PMID: 25929831. 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. Hu L et al. R558C NOTCH3 Mutation in a CADASIL Patient with Intracerebral Hemorrhage: A Case Report with Literature Review. J Stroke Cerebrovasc Dis. 2022 Jul;31(7):106541. Epub 2022 May 3. PMID: 35523050. 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. -
NOTCH3-related disorder Pathogenic:1
The NOTCH3 c.1672C>T variant is predicted to result in the amino acid substitution p.Arg558Cys. This variant was reported to be causative for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Chitnis et al. 2012. PubMed ID: 22218279; Ross et al. 2013. PubMed ID: 24086431; Yamamoto et al. 2009. PubMed ID: 19359623). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-15298084-G-A). Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant alters a cysteine residue and is located in the extracellular EGFr-like domain 14. Pathogenic variants in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGFr domains 7-34 have a much higher population frequency, and can predispose to a milder small-vessel disease, possibly even displaying incomplete or at least very late onset complete penetrance (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). 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
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See cases Pathogenic:1
ACMG classification criteria: PS4, PM1, PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at