ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.1918C>T (p.Arg640Cys)
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.1918C>T (p.Arg640Cys)
Variation ID: 870211 Accession: VCV000870211.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15186911 (GRCh38) [ NCBI UCSC ] 19: 15297722 (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 May 4, 2020 Jul 15, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.1918C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Arg640Cys missense NC_000019.10:g.15186911G>A NC_000019.9:g.15297722G>A NG_009819.1:g.19071C>T - Protein change
- R640C
- Other names
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- Canonical SPDI
- NC_000019.10:15186910: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) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 |
1489 | 1527 |
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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not provided (1) |
no classification provided
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- | RCV001089755.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2023 | RCV001288880.21 |
Submissions - Germline
Classification
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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
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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
(Mar 21, 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: SCV001476277.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. However, the variant … (more)
The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. However, the variant is also statistically more frequent in published patients with CADASIL (PMID: 28710804, 31915071, 32277177), suggesting this variant is associated with disease. This variant alters a critical location within the protein (EGF-like repeat domain 16), and is expected to severely affect function and cause disease. Pathogenic variants in the EGF-like repeat domains 7-34 have a higher population frequency than variants in the EGF-like repeat domains 1-6. Therefore, variants in domains 7-34 may be associated with milder disease or may possibly be non-penetrant (PMID: 27844030, 30032161). 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
(Dec 06, 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: SCV002172583.3
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 640 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 640 of the NOTCH3 protein (p.Arg640Cys). This variant is present in population databases (rs760768552, gnomAD 0.02%). This missense change has been observed in individuals with subcortical infarcts and leukoencephalopathy and lateral meningocele syndrome (PMID: 22664156, 28710804, 30279455, 32277177; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 870211). 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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Likely pathogenic
(Sep 01, 2022)
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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: SCV002585722.12
First in ClinVar: Oct 22, 2022 Last updated: Jul 15, 2024 |
Comment:
NOTCH3: PM1:Strong, PS4:Moderate, PP2
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - CureCADASIL
Accession: SCV001245246.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
Variant interpreted as Likely pathogenic and reported on 06-02-2008 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely pathogenic and reported on 06-02-2008 by Lab or GTR ID 1012. 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. (less)
Clinical Features:
Hypermetropia (present) , Abnormality of the lens (present) , Myopia (disease) (present) , Abnormality of the oral cavity (present) , Abnormality of the neck (present) … (more)
Hypermetropia (present) , Abnormality of the lens (present) , Myopia (disease) (present) , Abnormality of the oral cavity (present) , Abnormality of the neck (present) , Syncope (present) , Hypercholesterolemia (present) , Abnormal renal morphology (present) , Abnormality of the urethra (present) , Abnormality of the ureter (present) , Abnormality of muscle physiology (present) , Atrophic scars (present) , Memory impairment (present) , Bleeding with minor or no trauma (present) , Bruising susceptibility (present) , Anxiety (present) , Depressivity (present) (less)
Age: 40-49 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2008-06-02
Testing laboratory interpretation: Likely pathogenic
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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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Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. | Ni W | CNS neuroscience & therapeutics | 2022 | PMID: 35822697 |
Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. | Rutten JW | Neurology | 2020 | PMID: 32732295 |
Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. | Mukai M | Journal of human genetics | 2020 | PMID: 32277177 |
Investigating diagnostic sequencing techniques for CADASIL diagnosis. | Dunn PJ | Human genomics | 2020 | PMID: 31915071 |
Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. | Koriath C | Molecular psychiatry | 2020 | PMID: 30279455 |
Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. | Wang G | Journal of psychiatric research | 2019 | PMID: 30954774 |
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 |
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 |
Text-mined citations for rs760768552 ...
HelpRecord last updated Jul 15, 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.