NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys) AND Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 22, 2022
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:: RCV001253276.4

Allele description [Variation Report for NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)]

NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)

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.160C>T (p.Arg54Cys)

HGVS:

NC_000019.10:g.15197537G>A
NG_009819.1:g.8445C>T
NM_000435.3:c.160C>TMANE SELECT
NP_000426.2:p.Arg54Cys
NC_000019.9:g.15308348G>A
NM_000435.2:c.160C>T

Protein change:

R54C

Links:

dbSNP: rs1555730189

NCBI 1000 Genomes Browser:

rs1555730189

Molecular consequence:

NM_000435.3:c.160C>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
SCV001428913	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001760443	Genomics England Pilot Project, Genomics England	no assertion criteria provided (ACGS Guidelines, 2016)	Likely pathogenic	germline	clinical testing	Citation Link,
SCV002318670	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24139282, 32277177, 11102981, 26002683, 26270344, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001428913

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 27, 2017)

germline

clinical testing

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

SCV001760443

Genomics England Pilot Project, Genomics England

no assertion criteria provided

(ACGS Guidelines, 2016)

Likely pathogenic

germline

clinical testing

Citation Link,

SCV002318670

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 22, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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

Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients.

Mukai M, Mizuta I, Watanabe-Hosomi A, Koizumi T, Matsuura J, Hamano A, Tomimoto H, Mizuno T.

J Hum Genet. 2020 Aug;65(8):637-646. doi: 10.1038/s10038-020-0751-9. Epub 2020 Apr 10.

PubMed [citation]

PMID:: 32277177

See all PubMed Citations (6)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428913.1

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

From Genomics England Pilot Project, Genomics England, SCV001760443.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002318670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447791, PMID:11102981). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26270344, 24139282, 32277177, 26002683, 11102981). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.803>=0.6). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. 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

Last Updated: May 7, 2024

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