NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys) AND Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jun 3, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000778145.20

Allele description [Variation Report for NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys)]

NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys)

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.1630C>T (p.Arg544Cys)

Other names:

Chinese founder variant; p.Arg544Cys

HGVS:

NC_000019.10:g.15187315G>A
NG_009819.1:g.18667C>T
NM_000435.3:c.1630C>TMANE SELECT
NP_000426.2:p.Arg544Cys
NC_000019.9:g.15298126G>A
NM_000435.2:c.1630C>T

Protein change:

R544C

Links:

dbSNP: rs201118034

NCBI 1000 Genomes Browser:

rs201118034

Molecular consequence:

NM_000435.3:c.1630C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Synonyms:: 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
SCV000914276	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 5, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21852154, 24139282, 26308724, 23847153, 10371548, 19242647, 19252787, 23602593 Citation Link,
SCV000987226	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19242647, 20301673
SCV002058228	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:31792094,
SCV002517806	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002767997	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26308724, 30656190, 25741868
SCV006083208	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 3, 2025)	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, literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C.

Choi JC, Song SK, Lee JS, Kang SY, Kang JH.

J Stroke Cerebrovasc Dis. 2013 Feb;22(2):126-31. doi: 10.1016/j.jstrokecerebrovasdis.2011.07.002.

PubMed [citation]

PMID:: 21852154

Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Kim YE, Yoon CW, Seo SW, Ki CS, Kim YB, Kim JW, Bang OY, Lee KH, Kim GM, Chung CS, Na DL.

Neurobiol Aging. 2014 Mar;35(3):726.e1-6. doi: 10.1016/j.neurobiolaging.2013.09.004. Epub 2013 Oct 16.

PubMed [citation]

PMID:: 24139282

See all PubMed Citations (11)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914276.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The NOTCH3 c.1630C>T (p.Arg544Cys) missense variant has been reported extensively in the literature, particularly in individuals affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) of Asian descent, where the variant appears to be a founder variant (Lee et al. 2009; Choi et al. 2013; Liao et al. 2015). Across a selection of the available literature, the p.Arg544Cys variant has been identified in 155 individuals affected with CADASIL, including four individuals who were homozygous for the variant (Oberstein et al. 1999; Lee et al. 2009b; Choi et al. 2013; Soong et al. 2013; Kim et al. 2014; Liao et al. 2015). Of note, the expressivity of CADASIL varies in age of onset, severity of clinical symptoms and progression of disease (Rutten et al. 2000). The p.Arg544Cys variant was absent from 100 controls and is reported at a frequency of 0.003821 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Arg544Cys variant is classified as pathogenic for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

From GeneReviews, SCV000987226.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	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

From 3billion, SCV002058228.1

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

Description

The variant known to cause Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 in an autosomal dominant inheritance pattern. The variant the most common variant associated with CADASIL in the East Asian population (PMID: 25692567, 26308724, 31792094). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 32277177, 30906334, 25692567, 26308724, 31792094, PS4_S). A missense variant is a common mechanism associated with Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Mendelics, SCV002517806.1

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

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767997.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both loss of function and dominant negative have been suggested as mechanisms in CADASIL (MIM#125310), however lateral meningocele syndrome (MIM#130720) results from a gain of function (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The p.(Arg544Cys) variant is associated with a later age of onset and milder clinical features than other NOTCH3 variants (GeneReviews, PMID: 26308724). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v3) (8 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (83 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This is considered to be a founder variant in East Asian populations and is one of the most common NOTCH3 variants, having been identified in over 100 individuals and families with CADASIL (MIM#125310) (ClinVar, HGMD, LOVD, PMIDs: PMID: 26308724, 30656190). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV006083208.1

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

Description

PM1_strong, PP1 and PP4_strong

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

Last Updated: Jun 8, 2025

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