ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)
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.
Pathogenic(4); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)
Variation ID: 447862 Accession: VCV000447862.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15192020 (GRCh38) [ NCBI UCSC ] 19: 15302831 (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 Dec 19, 2017 May 12, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.619C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Arg207Cys missense NC_000019.10:g.15192020G>A NC_000019.9:g.15302831G>A NG_009819.1:g.13962C>T - Protein change
- R207C
- Other names
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- Canonical SPDI
- NC_000019.10:15192019: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 |
1487 | 1525 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000517748.36 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763039.10 | |
Likely pathogenic (1) |
no assertion criteria provided
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Nov 19, 2020 | RCV001374652.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV003330087.4 |
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
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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
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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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Likely 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: SCV000893516.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Mar 05, 2020)
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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: SCV001158574.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
Comment:
The NOTCH3 c.619C>T; p.Arg207Cys variant (rs775267348) is reported in the literature in multiple individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Matsushima 2017, … (more)
The NOTCH3 c.619C>T; p.Arg207Cys variant (rs775267348) is reported in the literature in multiple individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Matsushima 2017, Oberstein 1999, Singhal 2004). This variant is found on only two chromosomes (2/250308 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 447862). The arginine at codon 207 is moderately conserved and occurs in the fifth EGF-like domain, although computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. 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 the p.Arg207Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Dotti MT et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005 May;76(5):736-8. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Oberstein SA et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999 Jun 10;52(9):1913-5. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8. (less)
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Pathogenic
(Jul 17, 2019)
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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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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004037373.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The R207C variant in the NOTCH3 gene is a heterozygous missense variant, which results in the substitution of an arginine residue at the 207 position … (more)
The R207C variant in the NOTCH3 gene is a heterozygous missense variant, which results in the substitution of an arginine residue at the 207 position to cysteine. This variant localizes to coding exon 4 of the NOTCH3 gene (33 coding exons in total; NP_000426.2) and is part of the EGF-like 5 domain. In silico analyses are inconsistent in predicting the effect of this variant on protein structure and/ or function: it is predicted to be deleterious and damaging to protein structure and/ or function by PROVEAN but predicted to be tolerated by SIFT. This variant is present in the Genome Aggregation Database (gnomAD) at a very low frequency (2/250,308), indicating it is not a common benign variant in the populations represented in these databases. Mutations in NOTCH3 are associated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL) (OMIM#125310). This specific variant has been described to be disease causing in several cohorts of individuals with CADASIL (PMIDs: 27890607, 26305465, 25623805, 15834039, 10371548, 22664156), and is reported in the ClinVar database as Pathogenic/Likely Pathogenic (Variation ID: 447862). (less)
Clinical Features:
Stroke disorder (present) , Depression (present) , Atherosclerosis (present) , Paroxysmal atrial fibrillation (present)
Family history: yes
Age: 60-69 years
Sex: female
Ethnicity/Population group: European Caucasoid
Geographic origin: Ireland
Tissue: DNA
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Likely pathogenic
(Oct 04, 2023)
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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: SCV000617300.4
First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023 |
Comment:
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: 27890607, … (more)
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: 27890607, 31589614, 36535904, 35822697, 34297860, 31433517, 36401683, Moroz2018[CaseReport], 20935329, 16009764, 11102981, 15834039, 32277177, Dogan2023[casereport], 24844136) (less)
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Pathogenic
(Mar 24, 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
Accession: SCV000614321.5
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 (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with CADASIL. In some published literature, this variant is referred to as c.697C>T. 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
(Jan 31, 2024)
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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: SCV002225150.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 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 207 of the NOTCH3 protein (p.Arg207Cys). This variant is present in population databases (rs775267348, gnomAD 0.002%). This missense change has been observed in individuals with CADASIL (PMID: 15834039, 16009764, 20935329, 27890607). ClinVar contains an entry for this variant (Variation ID: 447862). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Apr 04, 2024)
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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: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809440.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Jan 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249853.21
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 19, 2020)
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no assertion criteria provided
Method: clinical testing
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CADASIL
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV001571575.1
First in ClinVar: Apr 22, 2021 Last updated: Apr 22, 2021 |
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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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Genotype-phenotype correlations of cysteine replacement in CADASIL. | Matsushima T | Neurobiology of aging | 2017 | PMID: 27890607 |
Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke. | Kilarski LL | PloS one | 2015 | PMID: 26305465 |
New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). | Abramycheva N | Journal of the neurological sciences | 2015 | PMID: 25623805 |
Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). | Testi S | Journal of the neurological sciences | 2012 | PMID: 22664156 |
NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. | Wang Z | Journal of neurology, neurosurgery, and psychiatry | 2011 | PMID: 20935329 |
Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. | Peters N | Archives of neurology | 2005 | PMID: 16009764 |
The spectrum of Notch3 mutations in 28 Italian CADASIL families. | Dotti MT | Journal of neurology, neurosurgery, and psychiatry | 2005 | PMID: 15834039 |
The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. | Singhal S | Brain : a journal of neurology | 2004 | PMID: 15229130 |
Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. | Escary JL | Human mutation | 2000 | PMID: 11102981 |
Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. | Oberstein SA | Neurology | 1999 | PMID: 10371548 |
Text-mined citations for rs775267348 ...
HelpRecord last updated May 12, 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.