NM_000435.3(NOTCH3):c.3658C>T (p.Arg1220Trp) AND none provided

Clinical significance:Uncertain significance (Last evaluated: Aug 7, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001285636.1

Allele description [Variation Report for NM_000435.3(NOTCH3):c.3658C>T (p.Arg1220Trp)]

NM_000435.3(NOTCH3):c.3658C>T (p.Arg1220Trp)

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.3658C>T (p.Arg1220Trp)
HGVS:
  • NC_000019.10:g.15179085G>A
  • NG_009819.1:g.26897C>T
  • NM_000435.3:c.3658C>TMANE SELECT
  • NP_000426.2:p.Arg1220Trp
  • NC_000019.9:g.15289896G>A
  • NM_000435.2:c.3658C>T
Protein change:
R1220W
Links:
dbSNP: rs115872852
NCBI 1000 Genomes Browser:
rs115872852
Molecular consequence:
  • NM_000435.3:c.3658C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001472101ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Aug 7, 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, SCV001472101.1

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

Description

The NOTCH3 c.3658C>T; p.Arg1220Trp variant (rs115872852), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 707700). This variant is found in the African population with an allele frequency of 0.12% (30/24834 alleles) in the Genome Aggregation Database. The arginine at codon 1220 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly 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). However, there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). Although the p.Arg1220Trp does not involve a cysteine residue, due to the lack of clinical and functional data, its clinical significance is uncertain. References: Muino E et al. Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Int J Mol Sci. 2017 Sep 13;18(9). pii: E1964. 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: Feb 6, 2021

Support Center