NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys) AND Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 4, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003330087.4

Allele description [Variation Report for NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)]

NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)

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.619C>T (p.Arg207Cys)

HGVS:

NC_000019.10:g.15192020G>A
NG_009819.1:g.13962C>T
NM_000435.3:c.619C>TMANE SELECT
NP_000426.2:p.Arg207Cys
NC_000019.9:g.15302831G>A
NM_000435.2:c.619C>T

Protein change:

R207C

Links:

dbSNP: rs775267348

NCBI 1000 Genomes Browser:

rs775267348

Molecular consequence:

NM_000435.3:c.619C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Synonyms:: Dementia, hereditary multi-infarct type; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1
Identifiers:: MONDO: MONDO:0000914; MedGen: C4551768; Orphanet: 136; OMIM: 125310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004037373	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 27890607, 26305465, 25623805, 15834039, 10371548, 22664156, 25741868
SCV004809440	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004037373

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2019)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004809440

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 4, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
European Caucasoid	germline	yes	1	not provided	not provided	1	yes	clinical testing

Citations

PubMed

Genotype-phenotype correlations of cysteine replacement in CADASIL.

Matsushima T, Conedera S, Tanaka R, Li Y, Yoshino H, Funayama M, Ikeda A, Hosaka Y, Okuzumi A, Shimada Y, Yamashiro K, Motoi Y, Nishioka K, Hattori N.

Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. doi: 10.1016/j.neurobiolaging.2016.10.026. Epub 2016 Nov 2.

PubMed [citation]

PMID:: 27890607

Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke.

Kilarski LL, Rutten-Jacobs LC, Bevan S, Baker R, Hassan A, Hughes DA, Markus HS; UK Young Lacunar Stroke DNA Study..

PLoS One. 2015;10(8):e0136352. doi: 10.1371/journal.pone.0136352.

PubMed [citation]

PMID:: 26305465
PMCID:: PMC4549151

See all PubMed Citations (7)

Details of each submission

From Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center, SCV004037373.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European Caucasoid	1	not provided	yes	clinical testing	PubMed (7)

Description

The R207C variant in the NOTCH3 gene is a heterozygous missense variant, which results in the substitution of an arginine residue at the 207 position to cysteine. This variant localizes to coding exon 4 of the NOTCH3 gene (33 coding exons in total; NP_000426.2) and is part of the EGF-like 5 domain. In silico analyses are inconsistent in predicting the effect of this variant on protein structure and/ or function: it is predicted to be deleterious and damaging to protein structure and/ or function by PROVEAN but predicted to be tolerated by SIFT. This variant is present in the Genome Aggregation Database (gnomAD) at a very low frequency (2/250,308), indicating it is not a common benign variant in the populations represented in these databases. Mutations in NOTCH3 are associated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL) (OMIM#125310). This specific variant has been described to be disease causing in several cohorts of individuals with CADASIL (PMIDs: 27890607, 26305465, 25623805, 15834039, 10371548, 22664156), and is reported in the ClinVar database as Pathogenic/Likely Pathogenic (Variation ID: 447862).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	DNA	validation		1	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809440.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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