ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.544C>T (p.Arg182Cys)
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.544C>T (p.Arg182Cys)
Variation ID: 9220 Accession: VCV000009220.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15192095 (GRCh38) [ NCBI UCSC ] 19: 15302906 (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 2, 2016 May 12, 2024 Nov 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.544C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Arg182Cys missense NC_000019.10:g.15192095G>A NC_000019.9:g.15302906G>A NG_009819.1:g.13887C>T Q9UM47:p.Arg182Cys - Protein change
- R182C
- Other names
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- Canonical SPDI
- NC_000019.10:15192094: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.
The Genome Aggregation Database (gnomAD) 0.00001
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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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2022 | RCV000009801.12 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Nov 25, 2023 | RCV000517955.34 |
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
(Aug 11, 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
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950078.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249854.19
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2, PP4, PS3:Supporting
Number of individuals with the variant: 6
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446573.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Vertigo (present) , Leukodystrophy (present) , Migraine (present)
Sex: female
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Pathogenic
(Aug 12, 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: SCV002581807.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM1_STR, PM6, PS3_SUP, PM2_SUP, PP2, PP3
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Number of individuals with the variant: 5
Sex: female
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Pathogenic
(Jul 12, 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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GeneDx
Accession: SCV001776645.3
First in ClinVar: Aug 11, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in multiple unrelated patients with clinical features of CADASIL referred for genetic testing at GeneDx and in published literature (Joutel et al., 2000; Dichgans … (more)
Observed in multiple unrelated patients with clinical features of CADASIL referred for genetic testing at GeneDx and in published literature (Joutel et al., 2000; Dichgans et al., 2000; Escary et al., 2000; Joutel et al., 2001; Singhal et al., 2004; Opherk et al., 2004; Peters et al., 2005; Wang et al., 2011; Chen et al., 2017; Mizuta et al., 2017; Paraskevas et al., 2018); Published functional studies demonstrate recapitulation of CADASIL phenotypes in a transgenic mouse model (Rutten et al., 2015); 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: 27781952, 14618173, 11755616, 15364702, 34335700, 17323840, 8878478, 28717674, 16796587, 29706439, 9388399, 16009764, 10371548, 27350778, 15229130, 11102981, 12810003, 20935329, 26856460, 28710804, 28991717, 33942994, 32277177, 24844136, 10854111, 10716263, 26715087) (less)
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Pathogenic
(Nov 04, 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
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175686.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The NOTCH3 c.544C>T variant is classified as PATHOGENIC (PS4, PM2_Supporting, PS2_supporting, PM1_Strong, PP3_moderate) The NOTCH3 c.544C>T variant is a single nucleotide change in exon 4/33 … (more)
The NOTCH3 c.544C>T variant is classified as PATHOGENIC (PS4, PM2_Supporting, PS2_supporting, PM1_Strong, PP3_moderate) The NOTCH3 c.544C>T variant is a single nucleotide change in exon 4/33 of the NOTCH3 gene, which is predicted to change the amino acid arginine at position 182 in the protein to cysteine. The variant has been reported in multiple individuals with a clinical presentation of CADASIL (PMID: 9388399, 15364702) (PS4) and is rare in population databases (PM2-supp). This variant has been reported in one affected patient with no family history of this condition (PMID:10716263) (PS2_supporting). This variant is located in the EGF-like 4 domain and results in a gain of a cysteine residue (PM1-strong). Computational predictions moderately support a deleterious effect on the gene or gene product (PP3_moderate). This variant is in dbSNP (rs28933697), has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID:9220) and has been reported as disease-causing in HGMD (CM961044). This variant has been listed 8 times on the NOTCH3 LOVD (less)
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Pathogenic
(Dec 01, 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: SCV000614313.5
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 of CADASIL, including at least one confirmed de novo. 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 25, 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: SCV002233185.3
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 182 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 182 of the NOTCH3 protein (p.Arg182Cys). This variant is present in population databases (rs28933697, gnomAD 0.007%). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 12395806, 16009764). ClinVar contains an entry for this variant (Variation ID: 9220). 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
(Sep 04, 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: SCV001160168.2
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The NOTCH3 c.544C>T; p.Arg182Cys variant (rs28933697), is reported in the literature in multiple individuals affected with CADASIL (Joutel 1997, Joutel 2000, Oberstein 1999). This variant … (more)
The NOTCH3 c.544C>T; p.Arg182Cys variant (rs28933697), is reported in the literature in multiple individuals affected with CADASIL (Joutel 1997, Joutel 2000, Oberstein 1999). This variant is reported as pathogenic in ClinVar (Variation ID: 9220), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 182 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.789). This variant lies with an EGF-like repeat domain, and pathogenic variants resulting in the gain or loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure (Dichgans 2000, Joutel 1997, Rutten 2016). Based on available information, the p.Arg182Cys variant is considered to be pathogenic. References: Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Joutel A et al. De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol. 2000 Mar;47(3):388-91. 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. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. (less)
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Pathogenic
(Mar 01, 2000)
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no assertion criteria provided
Method: literature only
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CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030022.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 02, 2016 |
Comment on evidence:
In 2 unrelated CADASIL1 (125310) patients, Joutel et al. (1996, 1997) observed a CGC-to-TGC transition in a different codon in exon N3 of the NOTCH3 … (more)
In 2 unrelated CADASIL1 (125310) patients, Joutel et al. (1996, 1997) observed a CGC-to-TGC transition in a different codon in exon N3 of the NOTCH3 gene that resulted in substitution of cys for arg (R182C) in the same EGF-like domain. Joutel et al. (2000) reported a patient who was thought to have CADASIL, although no first-degree relative was affected. The patient was found to carry a heterozygous arg182-to-cys mutation in the NOTCH3 gene; the mutation was absent in his parents, indicating a de novo mutation. They suggested that because of the occurrence of such cases, CADASIL may be more frequent than recognized. The frequency of the condition as a familial disorder is reflected in the fact that Joutel et al. (2000) found that more than 400 families had been identified since 1993. The patient with the arg182-to-cys mutation was a 55-year-old businessman who had experienced recurrent transient focal neurologic episodes, some suggestive of transient ischemic attacks and others of migrainous auras, dating back to the age of 32 years. At 48 years of age, he had a minor ischemic stroke with left facial asymmetry and weakness. Brain MRI showed extensive white matter abnormalities. Multiple sclerosis was suspected. At 53 years, he experienced a pure motor right-sided hemiplegia, which progressed over 5 days. Recovery was only partial, and the patient remained disabled with difficulties in walking and in moving his right hand. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035620.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037509.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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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: yes, unknown
Allele origin:
unknown
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GenomeConnect - CureCADASIL
Accession: SCV001156358.3
First in ClinVar: Feb 10, 2020 Last updated: Jan 01, 2022 |
Comment:
Variant interpreted as Pathogenic and reported, most recently, on 05-09-2018 by lab or GTR ID Athena Diagnostics. GenomeConnect - CureCADASIL assertions are reported exactly as … (more)
Variant interpreted as Pathogenic and reported, most recently, on 05-09-2018 by lab or GTR ID Athena Diagnostics. 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. Phenotypic details are available under supporting information. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Hypermetropia (present) , Abnormality of vision (present) , Myopia (present) , Abnormality of urine homeostasis (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2017-11-08
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of eye movement (present) , Hypermetropia (present) , Asthma (present) , Abnormality of reproductive system physiology (present) , Cognitive impairment (present) , Anxiety (present) … (more)
Abnormality of eye movement (present) , Hypermetropia (present) , Asthma (present) , Abnormality of reproductive system physiology (present) , Cognitive impairment (present) , Anxiety (present) , Depression (present) (less)
Age: 50-59 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2018-05-09
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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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 NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation. | Rutten JW | Acta neuropathologica communications | 2015 | PMID: 26715087 |
Intracerebral haemorrhage in CADASIL. A case report. | Werbrouck BF | Acta neurologica Belgica | 2006 | PMID: 17323840 |
Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. | Peters N | Archives of neurology | 2005 | PMID: 16009764 |
Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. | Opherk C | Brain : a journal of neurology | 2004 | PMID: 15364702 |
The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. | Singhal S | Brain : a journal of neurology | 2004 | PMID: 15229130 |
Diagnostic strategies in CADASIL. | Markus HS | Neurology | 2002 | PMID: 12395806 |
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. | Joutel A | Lancet (London, England) | 2001 | PMID: 11755616 |
Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. | Escary JL | Human mutation | 2000 | PMID: 11102981 |
Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. | Dichgans M | European journal of human genetics : EJHG | 2000 | PMID: 10854111 |
De novo mutation in the Notch3 gene causing CADASIL. | Joutel A | Annals of neurology | 2000 | PMID: 10716263 |
Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. | Oberstein SA | Neurology | 1999 | PMID: 10371548 |
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. | Joutel A | Lancet (London, England) | 1997 | PMID: 9388399 |
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. | Joutel A | Nature | 1996 | PMID: 8878478 |
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Text-mined citations for rs28933697 ...
HelpRecord last updated Jun 10, 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.