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

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Jul 4, 2021)
Last evaluated:
Oct 20, 2020
Accession:
VCV000804628.8
Variation ID:
804628
Description:
single nucleotide variant
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NM_000435.3(NOTCH3):c.2149C>T (p.Arg717Cys)

Allele ID
793759
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.12
Genomic location
19: 15185404 (GRCh38) GRCh38 UCSC
19: 15296215 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.15185404G>A
NC_000019.9:g.15296215G>A
NG_009819.1:g.20578C>T
NM_000435.3:c.2149C>T MANE Select NP_000426.2:p.Arg717Cys missense
Protein change
R717C
Other names
-
Canonical SPDI
NC_000019.10:15185403:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (A)

Allele frequency
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
1000 Genomes Project 0.00020
Links
dbSNP: rs144163298
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Jun 19, 2018 RCV001266935.1
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Oct 20, 2020 RCV000991701.4
Uncertain significance 1 no assertion criteria provided Apr 1, 2020 RCV001263185.1

Clinical features observed in individuals with this variant

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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
NOTCH3 - - GRCh38
GRCh37
836 855

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Dec 05, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV001143369.1
Submitted: (Sep 25, 2019)
Evidence details
Publications
PubMed (2)
Uncertain significance
(Jun 19, 2018)
criteria provided, single submitter
Method: clinical testing
Inborn genetic diseases
Allele origin: germline
Ambry Genetics
Accession: SCV001445116.1
Submitted: (Oct 09, 2020)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Oct 20, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV001563444.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Comment:
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 … (more)
Likely pathogenic
(Oct 01, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001501696.3
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(Apr 01, 2020)
no assertion criteria provided
Method: research
Vascular dementia
Allele origin: germline
Myllykangas group,University of Helsinki
Accession: SCV001250697.1
Submitted: (May 05, 2020)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Archetypal <i>NOTCH3</i> mutations frequent in public exome: implications for CADASIL. Rutten JW Annals of clinical and translational neurology 2016 PMID: 27844030
Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles. Liao YC PloS one 2015 PMID: 26308724

Text-mined citations for rs144163298...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021