ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.1672C>T (p.Arg558Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000435.3(NOTCH3):c.1672C>T (p.Arg558Cys)
Variation ID: 447794 Accession: VCV000447794.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15187273 (GRCh38) [ NCBI UCSC ] 19: 15298084 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 19, 2018 Feb 20, 2024 Nov 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.1672C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Arg558Cys missense NC_000019.10:g.15187273G>A NC_000019.9:g.15298084G>A NG_009819.1:g.18709C>T - Protein change
- R558C
- Other names
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- Canonical SPDI
- NC_000019.10:15187272:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NOTCH3 | - | - |
GRCh38 GRCh37 |
1486 | 1509 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2023 | RCV000517370.21 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 5, 2023 | RCV001526580.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2023 | RCV003419897.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763037.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 24, 2021 | RCV002252148.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Lateral meningocele syndrome Myofibromatosis, infantile, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893514.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737007.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Likely pathogenic
(May 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523155.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS4, PM1, PM2
Clinical Features:
Seizure (present) , Neonatal respiratory distress (present) , Seizure (present) , Neonatal respiratory distress (present)
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Likely pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573135.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Stroke disorder (present) , Pain (present)
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Pathogenic
(Jan 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580539.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM1_STR, PM2_SUP, PP2, PP3
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Number of individuals with the variant: 1
Sex: male
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Likely pathogenic
(Dec 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002038909.2
First in ClinVar: Dec 24, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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, 24844136, 31146726, Cebi2021[Article], Rustemoglu2021[article]) (less)
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Likely pathogenic
(Sep 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV004031460.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
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Likely pathogenic
(Sep 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934510.2
First in ClinVar: Sep 25, 2021 Last updated: Sep 09, 2023 |
Clinical Features:
Vasculitis (present) , Dementia (present)
Sex: male
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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NOTCH3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118345.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV000614235.5
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
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)
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). (less)
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002237220.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473496.3
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke. | Ilinca A | Stroke | 2020 | PMID: 32172663 |
Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. | Chen S | CNS neuroscience & therapeutics | 2017 | PMID: 28710804 |
Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. | Rutten JW | Annals of clinical and translational neurology | 2016 | PMID: 27844030 |
CADASIL: MRI may be normal in the fourth decade of life - a case report. | Samões R | Cephalalgia : an international journal of headache | 2016 | PMID: 26646783 |
A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients. | Fernández A | Journal of molecular neuroscience : MN | 2015 | PMID: 25929831 |
CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients. | Bianchi S | Journal of neurology | 2015 | PMID: 25344745 |
White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). | Craggs LJ | Neuropathology and applied neurobiology | 2014 | PMID: 23844775 |
NOTCH3 variants and risk of ischemic stroke. | Ross OA | PloS one | 2013 | PMID: 24086431 |
Brain microvascular accumulation and distribution of the NOTCH3 ectodomain and granular osmiophilic material in CADASIL. | Yamamoto Y | Journal of neuropathology and experimental neurology | 2013 | PMID: 23584202 |
CADASIL mutation and Balo concentric sclerosis: a link between demyelination and ischemia? | Chitnis T | Neurology | 2012 | PMID: 22218279 |
Neuropathological correlates of temporal pole white matter hyperintensities in CADASIL. | Yamamoto Y | Stroke | 2009 | PMID: 19359623 |
Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. | Tikka S | Brain : a journal of neurology | 2009 | PMID: 19174371 |
Cholinergic neuronal deficits in CADASIL. | Keverne JS | Stroke | 2007 | PMID: 17122431 |
Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. | Peters N | Archives of neurology | 2005 | PMID: 16009764 |
Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. | Opherk C | Brain : a journal of neurology | 2004 | PMID: 15364702 |
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. | Joutel A | Lancet (London, England) | 2001 | PMID: 11755616 |
Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. | Escary JL | Human mutation | 2000 | PMID: 11102981 |
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. | Joutel A | Lancet (London, England) | 1997 | PMID: 9388399 |
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. | Joutel A | Nature | 1996 | PMID: 8878478 |
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Text-mined citations for rs75068032 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.