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NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
6 (Most recent: Jul 4, 2021)
Last evaluated:
Mar 5, 2020
Accession:
VCV000447862.13
Variation ID:
447862
Description:
single nucleotide variant
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NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)

Allele ID
442159
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.12
Genomic location
19: 15192020 (GRCh38) GRCh38 UCSC
19: 15302831 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.15192020G>A
NC_000019.9:g.15302831G>A
NG_009819.1:g.13962C>T
NM_000435.3:c.619C>T MANE Select NP_000426.2:p.Arg207Cys missense
Protein change
R207C
Other names
-
Canonical SPDI
NC_000019.10:15192019:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Links
ClinGen: CA9263848
dbSNP: rs775267348
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 3 criteria provided, multiple submitters, no conflicts Mar 5, 2019 RCV000517748.5
Likely pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763039.1
Likely pathogenic 1 criteria provided, single submitter Mar 5, 2020 RCV001001376.3
Likely pathogenic 1 no assertion criteria provided Nov 19, 2020 RCV001374652.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
NOTCH3 - - GRCh38
GRCh37
835 854

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1
Lateral meningocele syndrome
Infantile myofibromatosis 2
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893516.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Likely pathogenic
(Oct 05, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000617300.2
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The R207C variant in the NOTCH3 gene has been reported previously in 2 unrelated individuals with clinical features of CADASIL (Escary et al., 2000; Matsushima … (more)
Pathogenic
(Mar 05, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV000614321.3
Submitted: (Sep 25, 2019)
Evidence details
Publications
PubMed (6)
Comment:
The variant disrupts a cysteine residue in an EGF-like repeat domain, which are important for the structure of this protein. Therefore it is expected to … (more)
Likely pathogenic
(Mar 05, 2020)
criteria provided, single submitter
Method: clinical testing
none provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158574.2
Submitted: (Dec 11, 2020)
Evidence details
Comment:
The NOTCH3 c.619C>T; p.Arg207Cys variant (rs775267348) is reported in the literature in multiple individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Matsushima 2017, … (more)
Pathogenic
(Jan 01, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001249853.6
Submitted: (Jul 04, 2021)
Evidence details
Likely pathogenic
(Nov 19, 2020)
no assertion criteria provided
Method: clinical testing
CADASIL
Allele origin: germline
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals
Accession: SCV001571575.1
Submitted: (Apr 15, 2021)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Genotype-phenotype correlations of cysteine replacement in CADASIL. Matsushima T Neurobiology of aging 2017 PMID: 27890607
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Abramycheva N Journal of the neurological sciences 2015 PMID: 25623805
The spectrum of Notch3 mutations in 28 Italian CADASIL families. Dotti MT Journal of neurology, neurosurgery, and psychiatry 2005 PMID: 15834039
The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Singhal S Brain : a journal of neurology 2004 PMID: 15229130
Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Escary JL Human mutation 2000 PMID: 11102981
Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Oberstein SA Neurology 1999 PMID: 10371548

Text-mined citations for rs775267348...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 11, 2021