ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.1565G>C (p.Cys522Ser)
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(1); Likely pathogenic(1); 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.1565G>C (p.Cys522Ser)
Variation ID: 1804902 Accession: VCV001804902.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15187922 (GRCh38) [ NCBI UCSC ] 19: 15298733 (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 24, 2022 Feb 20, 2024 Oct 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.1565G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Cys522Ser missense NC_000019.10:g.15187922C>G NC_000019.9:g.15298733C>G NG_009819.1:g.18060G>C - Protein change
- C522S
- Other names
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- Canonical SPDI
- NC_000019.10:15187921:C:G
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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.
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- 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 |
1487 | 1525 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 19, 2020 | RCV002471320.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV003482413.3 |
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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Uncertain significance
(Oct 19, 2020)
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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: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767211.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as a 3A-VUS Following criteria are met: 0103 - Gain of function and dominant negative … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as a 3A-VUS Following criteria are met: 0103 - Gain of function and dominant negative have been indicated as mechanisms of disease in this gene in association with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 1) (MIM#125310) (PMID: 19293235, PMID: 23649698, PMID: 30032161). Loss of function has also been reported but considered less likely (PMID: 24425116). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The position of the variant in the NOTCH3 gene is the most important determinant of CADASIL disease severity (PMID: 27844030, PMID: 30032161). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2.1.1 and v3). (SP) 0309 - An alternative amino acid change at the same position, p.(Cys522Trp), has been observed in gnomAD (v2.1.1) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is very highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional calcium-binding EGF-like domain. The addition or elimination of cysteine residues in the EGF-like repeat domains typically result in mismatched disulphide bridging and altered protein function (PMID: 32196841). (SP) 0705 - No comparable missense variants at the same position have previous evidence for pathogenicity. However, several cysteine-altering variants nearby and throughout the gene have been reported to cause disease (ClinVar, HGMD, LOVD3). (I) 0807- This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign (less)
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Pathogenic
(Jan 04, 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: SCV004229485.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in at least one individual with clinical features associated with CADASIL. This variant has not been reported in large, multi-ethnic … (more)
This variant has been identified in at least one individual with clinical features associated with 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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Likely pathogenic
(Oct 03, 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: SCV004562620.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The NOTCH3 c.1565G>C; p.Cys522Ser variant, is reported in the literature in two individuals affected with CADASIL (Rodriguez 2021, Zhang 2022). This variant is reported in … (more)
The NOTCH3 c.1565G>C; p.Cys522Ser variant, is reported in the literature in two individuals affected with CADASIL (Rodriguez 2021, Zhang 2022). This variant is reported in ClinVar (Variation ID: 1804902), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.976). 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.Cys522Ser variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Rodriguez CA et al. A novel Notch 3 mutation (pathogenic variant c.1565G>C) in CADASIL. Neurologia (Engl Ed). 2021 May 29:S0213-4853(21)00081-5. English, Spanish. PMID: 34074565. 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. Zhang R et al. Elderly CADASIL patients with intact neurological status. J Stroke. 2022 Sep;24(3):352-362. PMID: 36221938. (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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A novel Notch 3 mutation (pathogenic variant c.1565G>C) in CADASIL. | Rodriguez CA | Neurologia | 2022 | PMID: 34074565 |
Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. | Mancuso M | European journal of neurology | 2020 | PMID: 32196841 |
The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant. | Rutten JW | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30032161 |
Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. | Rutten JW | Annals of clinical and translational neurology | 2016 | PMID: 27844030 |
Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism. | Cognat E | Stroke | 2014 | PMID: 24425116 |
Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. | Monet-Leprêtre M | Brain : a journal of neurology | 2013 | PMID: 23649698 |
Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. | Monet-Leprêtre M | Brain : a journal of neurology | 2009 | PMID: 19293235 |
Text-mined citations for this variant ...
HelpRecord last updated May 08, 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.