NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys) AND none provided

Clinical significance:Likely pathogenic (Last evaluated: Mar 5, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001001376.3

Allele description [Variation Report for NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)]

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

Gene:
NOTCH3:notch receptor 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.12
Genomic location:
Preferred name:
NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)
HGVS:
  • NC_000019.10:g.15192020G>A
  • NG_009819.1:g.13962C>T
  • NM_000435.3:c.619C>TMANE SELECT
  • NP_000426.2:p.Arg207Cys
  • NC_000019.9:g.15302831G>A
  • NM_000435.2:c.619C>T
Protein change:
R207C
Links:
dbSNP: rs775267348
NCBI 1000 Genomes Browser:
rs775267348
Molecular consequence:
  • NM_000435.3:c.619C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001158574ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Mar 5, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158574.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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, Oberstein 1999, Singhal 2004). This variant is found on only two chromosomes (2/250308 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 447862). The arginine at codon 207 is moderately conserved and occurs in the fifth EGF-like domain, although computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. 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.Arg207Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Dotti MT et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005 May;76(5):736-8. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. 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. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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