ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.1258G>T (p.Gly420Cys)
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.1258G>T (p.Gly420Cys)
Variation ID: 447778 Accession: VCV000447778.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15189109 (GRCh38) [ NCBI UCSC ] 19: 15299920 (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 Feb 14, 2024 Nov 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.1258G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Gly420Cys missense NC_000019.10:g.15189109C>A NC_000019.9:g.15299920C>A NG_009819.1:g.16873G>T - Protein change
- G420C
- Other names
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- Canonical SPDI
- NC_000019.10:15189108:C: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 |
1471 | 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 (3) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2023 | RCV000517350.20 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Feb 22, 2018 | RCV000761306.10 |
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
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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
(Feb 22, 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
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000891283.1
First in ClinVar: Mar 24, 2019 Last updated: Mar 24, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 20, 2022)
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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: SCV001472640.3
First in ClinVar: Jan 26, 2021 Last updated: Mar 04, 2023 |
Comment:
The NOTCH3 c.1258G>T; p.Gly420Cys variant (rs1323608032) is reported in the literature in multiple individuals affected with CADASIL (Joutel 2001, Mehta 2013, Sathe 2009). This variant … (more)
The NOTCH3 c.1258G>T; p.Gly420Cys variant (rs1323608032) is reported in the literature in multiple individuals affected with CADASIL (Joutel 2001, Mehta 2013, Sathe 2009). This variant is in ClinVar (Variation ID: 447778), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 420 is highly conserved, and computational analyses (SIFT) predict that this variant is deleterious. 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.Gly420Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Joutel A et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001 Dec 15;358(9298):2049-51. Mehta S et al. Spontaneous cerebellar hemorrhage associated with a novel Notch3 mutation. J Clin Neurosci. 2013 Jul;20(7):1034-6. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Sathe S et al. Acute confusional migraine may be a presenting feature of CADASIL. Headache. 2009 Apr;49(4):590-6. (less)
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Pathogenic
(Mar 20, 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: SCV000614215.4
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in at least one individual with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general … (more)
This variant has been identified in at least one individual with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). 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
(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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Invitae
Accession: SCV002149835.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 420 of the NOTCH3 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 420 of the NOTCH3 protein (p.Gly420Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 11755616, 19245392, 23623146, 34851492; Invitae). ClinVar contains an entry for this variant (Variation ID: 447778). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV001245245.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
Variant interpreted as Pathogenic and reported on 09-22-2010 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 09-22-2010 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:
Abnormality of muscle physiology (present) , Morphological abnormality of the central nervous system (present) , Cognitive impairment (present) , Memory impairment (present) , Anxiety (present)
Age: 50-59 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2010-09-22
Testing laboratory interpretation: 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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NOTCH3 mutations in a cohort of Portuguese patients within CADASIL spectrum phenotype. | Almeida MR | Neurogenetics | 2022 | PMID: 34851492 |
Spontaneous cerebellar hemorrhage associated with a novel Notch3 mutation. | Mehta S | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2013 | PMID: 23623146 |
Acute confusional migraine may be a presenting feature of CADASIL. | Sathe S | Headache | 2009 | PMID: 19245392 |
CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. | Kalimo H | Brain pathology (Zurich, Switzerland) | 2002 | PMID: 12146805 |
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. | Joutel A | Lancet (London, England) | 2001 | PMID: 11755616 |
The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. | Joutel A | The Journal of clinical investigation | 2000 | PMID: 10712431 |
Text-mined citations for rs1323608032 ...
HelpRecord last updated Apr 20, 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.