ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.421C>T (p.Arg141Cys)
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.421C>T (p.Arg141Cys)
Variation ID: 447846 Accession: VCV000447846.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15192218 (GRCh38) [ NCBI UCSC ] 19: 15303029 (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 Aug 25, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.421C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Arg141Cys missense NC_000019.10:g.15192218G>A NC_000019.9:g.15303029G>A NG_009819.1:g.13764C>T - Protein change
- R141C
- Other names
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- Canonical SPDI
- NC_000019.10:15192217: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.
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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 |
1512 | 1550 |
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
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 (7) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000518361.40 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 20, 2022 | RCV001089753.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2021 | RCV002497000.8 | |
NOTCH3-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2024 | RCV004537854.2 |
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
(Jan 03, 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: SCV002059059.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant was co-segregated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 in multiple affected family members with additional meioses meeting moderate evidence levels … (more)
The variant was co-segregated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 11757773, 21737310, PP1_M). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11757773, 21737310, 19576955, 16580020, 28479817, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12482954, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.874, 3CNET: 0.861, PP3_P). A missense variant is a common mechanism associated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Stroke disorder (present)
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Pathogenic
(Jan 20, 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: SCV002580612.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM1, PM2_SUP, PP1, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jul 27, 2021)
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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: SCV002811110.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 21, 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: SCV001793803.2
First in ClinVar: Aug 21, 2021 Last updated: May 06, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on cell surface expression and protein trafficking (Karlstrom et al., 2002).; Not observed at significant frequency in large … (more)
Published functional studies demonstrate a damaging effect on cell surface expression and protein trafficking (Karlstrom et al., 2002).; Not observed at significant frequency in large population cohorts (gnomAD); 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: 31680059, 32188464, 17390743, 11757773, 16580020, 21737310, 19576955, 12482954, 15981641, 17235124, 10227618, 10371548, 11102981, 16009764, 11755616, 15364702, 9388399, 15229130, 10712431, 31433517, 32277177, 36047879, 34741685) (less)
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Pathogenic
(Jun 14, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225216.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PP2, PP3, PM1, PM2, PS3, PS4
Number of individuals with the variant: 2
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Pathogenic
(Dec 20, 2022)
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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: SCV000614299.5
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations … (more)
This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been previously reported as c.499C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12482954) 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 25, 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: SCV002212839.3
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 141 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 141 of the NOTCH3 protein (p.Arg141Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 9388399, 11757773, 16580020). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447846). 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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Pathogenic
(Aug 11, 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: SCV001160072.3
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The NOTCH3 c.421C>T; p.Arg141Cys variant is reported in the literature in numerous individuals with clinical diagnoses or personal and family histories indicative of CADASIL (Cappelli … (more)
The NOTCH3 c.421C>T; p.Arg141Cys variant is reported in the literature in numerous individuals with clinical diagnoses or personal and family histories indicative of CADASIL (Cappelli 2009, Joutel 1997, Kusaba 2007, Lee 2006, Murakami 2001, Onder 2017, Yadav 2013) and familial studies demonstrate that the variant cosegregates with disease (Murakami 2001, Yadav 2013). This variant is reported in ClinVar (Variation ID: 447846), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 141 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, this variant creates an additional cysteine in an EGF-like repeat domain, which is thought to lead to abnormal disulfide bridge formation and perturb protein function (Joutel 1997, Rutten 2016). Consistent with this notion, functional studies indicate that the p.Arg141Cys variant aggregates in the cytoplasm and is not efficiently processed and trafficked to the plasma membrane (Karlstrom 2002). Based on available information, this variant is considered to be pathogenic. References: Cappelli A et al. High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurosci Lett. 2009 Sep 22;462(2):176-8. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Karlstrom H et al. A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17119-24. Kusaba T et al. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clin Nephrol. 2007 Mar;67(3):182-7. Lee YC et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese. J Neurol Sci. 2006 Jul 15;246(1-2):111-5. Murakami T et al. Two Japanese CADASIL families with a R141C mutation in the Notch3 gene. Intern Med. 2001 Nov;40(11):1144-8. Onder H et al. R141C Mutation of NOTCH3 Gene in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. J Neurosci Rural Pract. 2017 Apr-Jun;8(2):301-303. Rutten JW et al. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016 Sep 28;3(11):844-853. Yadav S et al. The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Stroke Cerebrovasc Dis. 2013 Jan;22(1):28-31. (less)
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Pathogenic
(Mar 01, 2024)
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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: SCV004738748.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The NOTCH3 c.421C>T variant is predicted to result in the amino acid substitution p.Arg141Cys. The NOTCH3 gene sequence variant c.421C>T is predicted to result in … (more)
The NOTCH3 c.421C>T variant is predicted to result in the amino acid substitution p.Arg141Cys. The NOTCH3 gene sequence variant c.421C>T is predicted to result in the amino acid substitution p.Arg141Cys. This variant has been reported as causative for CADASIL in numerous unrelated patients, and functional studies support its pathogenicity (see, for example, Joutel et al. Lancet. 1997. PubMed ID: 9388399; Karlström et al. 2002. PubMed ID: 12482954; Cappelli et al. 2009. PubMed ID: 19576955). At PreventionGenetics, we previously identified this variant in other patients with a diagnosis of CADASIL. 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 EGF-like domain three. Pathogenic variants in EGF-like domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). We classify this variant as pathogenic. (less)
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Pathogenic
(Jun 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: SCV002498447.14
First in ClinVar: Apr 11, 2022 Last updated: Aug 04, 2024 |
Comment:
NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2, PP4
Number of individuals with the variant: 3
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Pathogenic
(May 27, 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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197010.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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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: SCV001245241.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
Variant interpreted as Pathogenic and reported most recently on 05/13/2013 by Lab or GTR ID 1012. The variant was also interpreted as Pathogenic by Lab … (more)
Variant interpreted as Pathogenic and reported most recently on 05/13/2013 by Lab or GTR ID 1012. The variant was also interpreted as Pathogenic by Lab or GTR ID 239772 on 80-16-2017. 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)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Myopia (disease) (present) , Encephalopathy (present)
Age: 30-39 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2010-01-19
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the large intestine (present) , Delayed puberty (present) , Goiter (present) , Hyperthyroidism (present)
Age: 20-29 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2013-05-13
Testing laboratory interpretation: Pathogenic
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Hyperthyroidism (present)
Age: 30-39 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2009-11-30
Testing laboratory interpretation: Pathogenic
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Behavioral abnormality (present) , Confusion (present) , Fatigue (present)
Age: 60-69 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2010-09-09
Testing laboratory interpretation: Pathogenic
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Myopia (disease) (present) , Encephalopathy (present) , Memory impairment (present) , Seizures (present) , Bruising susceptibility (present) , Abnormality of thrombocytes (present) , Autoimmunity (present)
Age: 40-49 years
Sex: female
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2017-08-16
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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Imaging Characteristics for Predicting Cognitive Impairment in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. | Taniguchi A | Frontiers in aging neuroscience | 2022 | PMID: 35754959 |
A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan. | Shindo A | Frontiers in aging neuroscience | 2020 | PMID: 32765252 |
Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. | Mukai M | Journal of human genetics | 2020 | PMID: 32277177 |
The CADASIL Scale-J, A Modified Scale to Prioritize Access to Genetic Testing for Japanese CADASIL-Suspected Patients. | Koizumi T | Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | 2019 | PMID: 30956055 |
The role of clinical and neuroimaging features in the diagnosis of CADASIL. | Bersano A | Journal of neurology | 2018 | PMID: 30311053 |
New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan. | Mizuta I | Journal of the neurological sciences | 2017 | PMID: 28991717 |
Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. | Chen S | CNS neuroscience & therapeutics | 2017 | PMID: 28710804 |
R141C Mutation of NOTCH3 Gene in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. | Onder H | Journal of neurosciences in rural practice | 2017 | PMID: 28479817 |
Evaluation of NOTCH3 Pro167Ser Variation in a Japanese Family with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. | Mizuno T | Dementia and geriatric cognitive disorders extra | 2016 | PMID: 27350778 |
The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). | Yadav S | Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | 2013 | PMID: 21737310 |
High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). | Cappelli A | Neuroscience letters | 2009 | PMID: 19576955 |
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and right-to-left shunt: lack of evidence for an association in a prevalence study. | Mazzucco S | European neurology | 2009 | PMID: 18948701 |
Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). | Kusaba T | Clinical nephrology | 2007 | PMID: 17390743 |
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese. | Lee YC | Journal of the neurological sciences | 2006 | PMID: 16580020 |
A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. | Karlström H | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12482954 |
Two Japanese CADASIL families with a R141C mutation in the Notch3 gene. | Murakami T | Internal medicine (Tokyo, Japan) | 2001 | PMID: 11757773 |
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. | Joutel A | Lancet (London, England) | 2001 | PMID: 11755616 |
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. | Joutel A | Lancet (London, England) | 1997 | PMID: 9388399 |
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Text-mined citations for rs1174625611 ...
HelpRecord last updated Sep 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.