NM_000435.3(NOTCH3):c.1345C>T (p.Arg449Cys) AND none provided

Clinical significance:Likely pathogenic (Last evaluated: Mar 27, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001289876.1

Allele description [Variation Report for NM_000435.3(NOTCH3):c.1345C>T (p.Arg449Cys)]

NM_000435.3(NOTCH3):c.1345C>T (p.Arg449Cys)

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.1345C>T (p.Arg449Cys)
HGVS:
  • NC_000019.10:g.15189022G>A
  • NG_009819.1:g.16960C>T
  • NM_000435.3:c.1345C>TMANE SELECT
  • NP_000426.2:p.Arg449Cys
  • NC_000019.9:g.15299833G>A
  • NM_000435.2:c.1345C>T
Protein change:
R449C
Links:
dbSNP: rs762734007
NCBI 1000 Genomes Browser:
rs762734007
Molecular consequence:
  • NM_000435.3:c.1345C>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
SCV001477875ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Mar 27, 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, SCV001477875.1

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

Description

The NOTCH3 c.1345C>T; p.Arg449Cys variant is reported in the literature in association with CADASIL, but without specific patient information (Kalimo 2002). This variant is reported in ClinVar (Variation ID: 810777), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 449 is highly conserved, occurs in an EGF-like domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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.Arg449Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Kalimo H et al. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002 Jul;12(3):371-84. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.

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

Last Updated: Apr 18, 2021

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