NM_000435.3(NOTCH3):c.1918C>T (p.Arg640Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 6, 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:: RCV001288880.25

Allele description [Variation Report for NM_000435.3(NOTCH3):c.1918C>T (p.Arg640Cys)]

NM_000435.3(NOTCH3):c.1918C>T (p.Arg640Cys)

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.1918C>T (p.Arg640Cys)

HGVS:

NC_000019.10:g.15186911G>A
NG_009819.1:g.19071C>T
NM_000435.3:c.1918C>TMANE SELECT
NP_000426.2:p.Arg640Cys
NC_000019.9:g.15297722G>A
NC_000019.9:g.15297722G>A
NM_000435.2:c.1918C>T

Protein change:

R640C

Links:

dbSNP: rs760768552

NCBI 1000 Genomes Browser:

rs760768552

Molecular consequence:

NM_000435.3:c.1918C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001476277	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Mar 21, 2023)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 35822697, 31915071, 28710804, 30954774, 27844030, 30279455, 32277177, 32732295, 26467025
SCV002172583	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22664156, 28710804, 30279455, 32277177, 28492532
SCV002585722	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Sep 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001476277

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Mar 21, 2023)

unknown

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV002172583

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 6, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002585722

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Sep 1, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations.

Ni W, Zhang Y, Zhang L, Xie JJ, Li HF, Wu ZY.

CNS Neurosci Ther. 2022 Nov;28(11):1779-1789. doi: 10.1111/cns.13917. Epub 2022 Jul 13.

PubMed [citation]

PMID:: 35822697
PMCID:: PMC9532899

Investigating diagnostic sequencing techniques for CADASIL diagnosis.

Dunn PJ, Maksemous N, Smith RA, Sutherland HG, Haupt LM, Griffiths LR.

Hum Genomics. 2020 Jan 8;14(1):2. doi: 10.1186/s40246-019-0255-x.

PubMed [citation]

PMID:: 31915071
PMCID:: PMC6950909

See all PubMed Citations (11)

Details of each submission

From Athena Diagnostics, SCV001476277.3

#	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 higher than would generally be expected for pathogenic variants in this gene. However, the variant is also statistically more frequent in published patients with CADASIL (PMID: 28710804, 31915071, 32277177), suggesting this variant is associated with disease. This variant alters a critical location within the protein (EGF-like repeat domain 16), and is expected to severely affect function and cause disease. Pathogenic variants in the EGF-like repeat domains 7-34 have a higher population frequency than variants in the EGF-like repeat domains 1-6. Therefore, variants in domains 7-34 may be associated with milder disease or may possibly be non-penetrant (PMID: 27844030, 30032161). 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002172583.3

#	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 640 of the NOTCH3 protein (p.Arg640Cys). This variant is present in population databases (rs760768552, gnomAD 0.02%). This missense change has been observed in individuals with subcortical infarcts and leukoencephalopathy and lateral meningocele syndrome (PMID: 22664156, 28710804, 30279455, 32277177; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 870211). 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, SCV002585722.15

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

Description

NOTCH3: PM1:Strong, PS4:Moderate, PP2

#	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

Last Updated: Oct 20, 2024

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