NM_000435.3(NOTCH3):c.397C>T (p.Arg133Cys) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000516340.36

Allele description [Variation Report for NM_000435.3(NOTCH3):c.397C>T (p.Arg133Cys)]

NM_000435.3(NOTCH3):c.397C>T (p.Arg133Cys)

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.397C>T (p.Arg133Cys)

Other names:

Finnish founder variant

HGVS:

NC_000019.10:g.15192242G>A
NG_009819.1:g.13740C>T
NM_000435.3:c.397C>TMANE SELECT
NP_000426.2:p.Arg133Cys
NC_000019.9:g.15303053G>A
NM_000435.2:c.397C>T
Q9UM47:p.Arg133Cys

Protein change:

R133C; ARG133CYS

Links:

UniProtKB: Q9UM47#VAR_012876; OMIM: 600276.0008; dbSNP: rs137852642

NCBI 1000 Genomes Browser:

rs137852642

Molecular consequence:

NM_000435.3:c.397C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

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
SCV000614294	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Feb 28, 2022)	unknown	clinical testing	PubMed (24) [See all records that cite these PMIDs] 28534048, 28334938, 32277177, 25604251, 11715067, 26261665, 22019870, 11771160, 19417009, 15350543, 25819272, 11486103, 10227618, 10371548, 10854111, 11755616, 12810003, 15364702, 16009764, 22623959, 10969905, 19825845, 9388399, 26467025
SCV001160148	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Apr 21, 2022)	germline	clinical testing	Citation Link,
SCV001746557	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2021)	germline	clinical testing	Citation Link,
SCV001777429	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 31, 2023)	germline	clinical testing	Citation Link,
SCV002214936	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10969905, 22019870, 28334938, 28492532
SCV004225227	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 29, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15378071, 19417009, 19825845, 34335700, 25741868

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

The First Report of CADASIL in Peru: Olfactory Dysfunction on Initial Presentation.

Vishnevetsky A, Inca-Martinez M, Milla-Neyra K, Barrientos-Iman DM, Cornejo-Herrera I, Cosentino C, Cornejo-Olivas M.

eNeurologicalSci. 2016 Dec;5:15-19. doi: 10.1016/j.ensci.2016.09.001. Epub 2016 Sep 28.

PubMed [citation]

PMID:: 28534048
PMCID:: PMC5438170

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 (28)

Details of each submission

From Athena Diagnostics Inc, SCV000614294.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

Description

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in at least one individual with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant causes protein aggregation and ER retention, resulting in impaired cell proliferation (PMID: 19825845). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain.

#	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, SCV001160148.4

#	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.397C>T; p.Arg133Cys variant (rs137852642) has been described in multiple individuals affected with CADASIL (Joutel 1997, Maclean 2005, Mykkanen 2004). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 9225), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 133 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In vitro characterization of this variant protein demonstrates increased spontaneous multimerization compared to wild-type (Opherk 2009). Based on available information, this variant is considered to be pathogenic. References: Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Maclean A et al. Spontaneous lobar haemorrhage in CADASIL. J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):456-7. Mykkanen K et al. Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet. 2004 Oct;12(10):813-9. Opherk C et al. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet. 2009 Aug 1;18(15):2761-7.

#	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, SCV001746557.14

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

From GeneDx, SCV001777429.2

#	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 suggest that the R133C impacts protein function (Opherk et al., 2009; Takahashi et al., 2010; Wollenweber et al., 2015); 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: 10854111, 26261665, 11771160, 25819272, 15378071, 15364702, 16009764, 9388399, 15350543, 19417009, 19825845, 10969905, 11715067, 15716553, 22623959, 22019870, 11486103, 25604251, 28334938, 28534048, 10371548, 12810003, 11755616, 31571467, 31554780, 30402942, 31720972, 34335700, 34008892, 15143298, 10609671, 36047879, 32555735, 34741685, 10766655, 30392756, 16877080, 32277177, 24844136)

#	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, SCV002214936.3

#	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 133 of the NOTCH3 protein (p.Arg133Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CADASIL (PMID: 10969905, 22019870, 28334938). ClinVar contains an entry for this variant (Variation ID: 9225). 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 Mayo Clinic Laboratories, Mayo Clinic, SCV004225227.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

PP3, PP4, PP5, PM1, 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

Last Updated: Apr 20, 2024

ClinVar

Relating variation to medicine