NM_000435.3(NOTCH3):c.421C>T (p.Arg141Cys) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 25, 2024
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:: RCV000518361.40

Allele description

NM_000435.3(NOTCH3):c.421C>T (p.Arg141Cys)

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.421C>T (p.Arg141Cys)

HGVS:

NC_000019.10:g.15192218G>A
NG_009819.1:g.13764C>T
NM_000435.3:c.421C>TMANE SELECT
NP_000426.2:p.Arg141Cys
NC_000019.9:g.15303029G>A
NM_000435.2:c.421C>T

Protein change:

R141C

Links:

dbSNP: rs1174625611

NCBI 1000 Genomes Browser:

rs1174625611

Molecular consequence:

NM_000435.3:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

sister chromatid cohesion protein DCC1 isoform X1 [Homo sapiens]
sister chromatid cohesion protein DCC1 isoform X1 [Homo sapiens]
gi|530389325|ref|XP_005251122.1|

Protein
ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit, partial (chloropl...
ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit, partial (chloroplast) [Nemosenecio nikoensis]
gi|2105314931|dbj|BCU08606.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000614299	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 20, 2022)	unknown	clinical testing	PubMed (19) [See all records that cite these PMIDs] 28479817, 27350778, 28991717, 30956055, 30311053, 28710804, 32277177, 32765252, 35754959, 9388399, 12482954, 17390743, 11755616, 18948701, 11757773, 16580020, 19576955, 21737310, 26467025
SCV001160072	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Aug 11, 2023)	germline	clinical testing	Citation Link,
SCV001793803	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 21, 2023)	germline	clinical testing	Citation Link,
SCV002212839	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9388399, 11757773, 16580020, 28492532
SCV002498447	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2022)	germline	clinical testing	Citation Link,
SCV004225216	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11755616, 12482954, 21737310, 28479817, 32277177, 9388399, 25741868
SCV005197010	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2022)	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	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evaluation of NOTCH3 Pro167Ser Variation in a Japanese Family with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Mizuno T, Mizuta I, Tomimoto H.

Dement Geriatr Cogn Dis Extra. 2016 May-Aug;6(2):183-4. doi: 10.1159/000445499. No abstract available.

PubMed [citation]

PMID:: 27350778
PMCID:: PMC4913764

New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan.

Mizuta I, Watanabe-Hosomi A, Koizumi T, Mukai M, Hamano A, Tomii Y, Kondo M, Nakagawa M, Tomimoto H, Hirano T, Uchino M, Onodera O, Mizuno T.

J Neurol Sci. 2017 Oct 15;381:62-67. doi: 10.1016/j.jns.2017.08.009. Epub 2017 Aug 8.

PubMed [citation]

PMID:: 28991717

See all PubMed Citations (21)

Details of each submission

From Athena Diagnostics, SCV000614299.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been previously reported as c.499C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12482954) This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160072.3

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

Description

The NOTCH3 c.421C>T; p.Arg141Cys variant is reported in the literature in numerous individuals with clinical diagnoses or personal and family histories indicative of CADASIL (Cappelli 2009, Joutel 1997, Kusaba 2007, Lee 2006, Murakami 2001, Onder 2017, Yadav 2013) and familial studies demonstrate that the variant cosegregates with disease (Murakami 2001, Yadav 2013). This variant is reported in ClinVar (Variation ID: 447846), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 141 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, this variant creates an additional cysteine in an EGF-like repeat domain, which is thought to lead to abnormal disulfide bridge formation and perturb protein function (Joutel 1997, Rutten 2016). Consistent with this notion, functional studies indicate that the p.Arg141Cys variant aggregates in the cytoplasm and is not efficiently processed and trafficked to the plasma membrane (Karlstrom 2002). Based on available information, this variant is considered to be pathogenic. References: Cappelli A et al. High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurosci Lett. 2009 Sep 22;462(2):176-8. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Karlstrom H et al. A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17119-24. Kusaba T et al. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Clin Nephrol. 2007 Mar;67(3):182-7. Lee YC et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese. J Neurol Sci. 2006 Jul 15;246(1-2):111-5. Murakami T et al. Two Japanese CADASIL families with a R141C mutation in the Notch3 gene. Intern Med. 2001 Nov;40(11):1144-8. Onder H et al. R141C Mutation of NOTCH3 Gene in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. J Neurosci Rural Pract. 2017 Apr-Jun;8(2):301-303. Rutten JW et al. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016 Sep 28;3(11):844-853. Yadav S et al. The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Stroke Cerebrovasc Dis. 2013 Jan;22(1):28-31.

#	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 GeneDx, SCV001793803.2

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

Description

Published functional studies demonstrate a damaging effect on cell surface expression and protein trafficking (Karlstrom et al., 2002).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31680059, 32188464, 17390743, 11757773, 16580020, 21737310, 19576955, 12482954, 15981641, 17235124, 10227618, 10371548, 11102981, 16009764, 11755616, 15364702, 9388399, 15229130, 10712431, 31433517, 32277177, 36047879, 34741685)

#	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 Invitae, SCV002212839.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 141 of the NOTCH3 protein (p.Arg141Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 9388399, 11757773, 16580020). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447846). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002498447.14

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

Description

NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2, PP4

#	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		3	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004225216.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (7)

Description

PP1, PP2, PP3, PM1, PM2, PS3, PS4

#	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		2	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197010.1

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

Last Updated: Sep 16, 2024

Relating variation to medicine