NM_000435.3(NOTCH3):c.2149C>T (p.Arg717Cys) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(2) (Last evaluated: Oct 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000991701.4

Allele description [Variation Report for NM_000435.3(NOTCH3):c.2149C>T (p.Arg717Cys)]

NM_000435.3(NOTCH3):c.2149C>T (p.Arg717Cys)

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.2149C>T (p.Arg717Cys)
HGVS:
  • NC_000019.10:g.15185404G>A
  • NG_009819.1:g.20578C>T
  • NM_000435.3:c.2149C>TMANE SELECT
  • NP_000426.2:p.Arg717Cys
  • NC_000019.9:g.15296215G>A
  • NM_000435.2:c.2149C>T
Protein change:
R717C
Links:
dbSNP: rs144163298
NCBI 1000 Genomes Browser:
rs144163298
Molecular consequence:
  • NM_000435.3:c.2149C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001143369Athena Diagnostics Inccriteria provided, single submitter
Uncertain significance
(Dec 5, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001501696CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Likely pathogenic
(Oct 1, 2020)
germlineclinical testing

Citation Link,

SCV001563444Invitaecriteria provided, single submitter
Uncertain significance
(Oct 20, 2020)
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 providedgermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL.

Rutten JW, Dauwerse HG, Gravesteijn G, van Belzen MJ, van der Grond J, Polke JM, Bernal-Quiros M, Lesnik Oberstein SA.

Ann Clin Transl Neurol. 2016 Nov;3(11):844-853.

PubMed [citation]
PMID:
27844030
PMCID:
PMC5099530

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
See all PubMed Citations (4)

Details of each submission

From Athena Diagnostics Inc, SCV001143369.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001501696.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV001563444.1

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

Description

This sequence change replaces arginine with cysteine at codon 717 of the NOTCH3 protein (p.Arg717Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs144163298, ExAC 0.005%). This variant has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 26308724). ClinVar contains an entry for this variant (Variation ID: 804628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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