NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 31, 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:: RCV000517748.36

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)

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
SCV000614321	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Mar 24, 2023)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20935329, 16009764, 25623805, 27890607, 10371548, 15229130, 15834039, 11102981, 26467025
SCV000617300	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 4, 2023)	germline	clinical testing	Citation Link,
SCV001158574	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Mar 5, 2020)	germline	clinical testing	Citation Link,
SCV001249853	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2019)	germline	clinical testing	Citation Link,
SCV002225150	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15834039, 16009764, 20935329, 27890607, 28492532

Help

Summary from all submissions

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

Citations

PubMed

New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).

Abramycheva N, Stepanova M, Kalashnikova L, Zakharova M, Maximova M, Tanashyan M, Lagoda O, Fedotova E, Klyushnikov S, Konovalov R, Sakharova A, Illarioshkin S.

J Neurol Sci. 2015 Feb 15;349(1-2):196-201. doi: 10.1016/j.jns.2015.01.018. Epub 2015 Jan 17.

PubMed [citation]

PMID:: 25623805

Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group.

Oberstein SA, Ferrari MD, Bakker E, van Gestel J, Kneppers AL, Frants RR, Breuning MH, Haan J.

Neurology. 1999 Jun 10;52(9):1913-5.

PubMed [citation]

PMID:: 10371548

See all PubMed Citations (10)

Details of each submission

From Athena Diagnostics, SCV000614321.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with CADASIL. In some published literature, this variant is referred to as c.697C>T. 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 GeneDx, SCV000617300.4

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

Description

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: 27890607, 31589614, 36535904, 35822697, 34297860, 31433517, 36401683, Moroz2018[CaseReport], 20935329, 16009764, 11102981, 15834039, 32277177, Dogan2023[casereport], 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158574.2

#	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.619C>T; p.Arg207Cys variant (rs775267348) is reported in the literature in multiple individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Matsushima 2017, Oberstein 1999, Singhal 2004). This variant is found on only two chromosomes (2/250308 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 447862). The arginine at codon 207 is moderately conserved and occurs in the fifth EGF-like domain, although computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Arg207Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Dotti MT et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005 May;76(5):736-8. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Oberstein SA et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999 Jun 10;52(9):1913-5. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8.

#	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, SCV001249853.21

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

From Invitae, SCV002225150.3

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the NOTCH3 protein (p.Arg207Cys). This variant is present in population databases (rs775267348, gnomAD 0.002%). This missense change has been observed in individuals with CADASIL (PMID: 15834039, 16009764, 20935329, 27890607). ClinVar contains an entry for this variant (Variation ID: 447862). 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

Last Updated: Jun 2, 2024

ClinVar

Relating variation to medicine