NM_000435.3(NOTCH3):c.3182G>A (p.Cys1061Tyr) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 14, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000485488.4

Allele description [Variation Report for NM_000435.3(NOTCH3):c.3182G>A (p.Cys1061Tyr)]

NM_000435.3(NOTCH3):c.3182G>A (p.Cys1061Tyr)

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.3182G>A (p.Cys1061Tyr)
HGVS:
  • NC_000019.10:g.15180217C>T
  • NG_009819.1:g.25765G>A
  • NM_000435.3:c.3182G>AMANE SELECT
  • NP_000426.2:p.Cys1061Tyr
  • NC_000019.9:g.15291028C>T
  • NM_000435.2:c.3182G>A
Protein change:
C1061Y
Links:
dbSNP: rs1064794216
NCBI 1000 Genomes Browser:
rs1064794216
Molecular consequence:
  • NM_000435.3:c.3182G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000568237GeneDxcriteria provided, single submitter
Likely pathogenic
(Mar 22, 2018)
germlineclinical testing

Citation Link,

SCV000614278Athena Diagnostics Inccriteria provided, single submitter
Pathogenic
(May 14, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression.

Zhang X, Meng H, Blaivas M, Rushing EJ, Moore BE, Schwartz J, Lopes MB, Worrall BB, Wang MM.

Transl Stroke Res. 2012 Mar;3(1):138-45. doi: 10.1007/s12975-011-0112-2. Epub 2011 Oct 20.

PubMed [citation]
PMID:
22639698
PMCID:
PMC3358806

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26467025
PMCID:
PMC4737317

Details of each submission

From GeneDx, SCV000568237.4

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

Description

The C1061Y variant in the NOTCH3 gene has been reported previously in association with CADASIL (Zhang et al., 2012). The C1061Y variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C1061Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The C1061Y variant is a strong candidate for a pathogenic variant.

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

From Athena Diagnostics Inc, SCV000614278.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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 severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data. Reported in a patient with CADASIL.

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

Last Updated: Nov 27, 2021

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