VCV000447830.24 - ClinVar

NM_000435.3(NOTCH3):c.3226C>T (p.Arg1076Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000435.3(NOTCH3):c.3226C>T (p.Arg1076Cys)

Variation ID: 447830 Accession: VCV000447830.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.12 19: 15180173 (GRCh38) [ NCBI UCSC ] 19: 15290984 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Oct 20, 2024	Sep 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000435.3:c.3226C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000426.2:p.Arg1076Cys	missense
NC_000019.10:g.15180173G>A
NC_000019.9:g.15290984G>A
NG_009819.1:g.25809C>T

Protein change

R1076C

Other names

Canonical SPDI

NC_000019.10:15180172:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA404513546 dbSNP: rs1438626607 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NOTCH3		-	-	GRCh38 GRCh37	1538	1576

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 27, 2022	RCV000518259.22
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Likely pathogenic (1)	criteria provided, single submitter	Feb 21, 2020	RCV001197703.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368482.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_MOD,PM1,PM2,PP2,PP3.
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000614279.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 31, 2022	Publications: PubMed (11) PubMed: 11571335‚ 26308724‚ 20038773‚ 21616505‚ 22878905‚ 15827866‚ 19180562‚ 25344745‚ 18803652‚ 12861102‚ 15834039 Comment: 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 CADASIL. … (more) 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 CADASIL. 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. (less)
Pathogenic (Sep 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002246398.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 11571335‚ 12861102‚ 15827866‚ 15834039‚ 22878905 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 447830). This variant is also known as R1075C. This missense change has been observed in individuals with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 11571335, 12861102, 15827866, 15834039, 22878905; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the NOTCH3 protein (p.Arg1076Cys). (less)
Likely pathogenic (Sep 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002585721.15 First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024	Comment: NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2 Number of individuals with the variant: 2

Comment:

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 CADASIL. 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.

Comment:

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 447830). This variant is also known as R1075C. This missense change has been observed in individuals with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 11571335, 12861102, 15827866, 15834039, 22878905; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the NOTCH3 protein (p.Arg1076Cys).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles.	Liao YC	PloS one	2015	PMID: 26308724
CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients.	Bianchi S	Journal of neurology	2015	PMID: 25344745
Effects of cerebrolysin administration on oxidative stress-induced apoptosis in lymphocytes from CADASIL patients.	Formichi P	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2013	PMID: 22878905
NOTCH3 gene mutations in subjects clinically suspected of CADASIL.	Mosca L	Journal of the neurological sciences	2011	PMID: 21616505
Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients.	Pantoni L	Neurology	2010	PMID: 20038773
Apoptosis in CADASIL: an in vitro study of lymphocytes and fibroblasts from a cohort of Italian patients.	Formichi P	Journal of cellular physiology	2009	PMID: 19180562
Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.	Piccirillo G	European journal of neurology	2008	PMID: 18803652
The spectrum of Notch3 mutations in 28 Italian CADASIL families.	Dotti MT	Journal of neurology, neurosurgery, and psychiatry	2005	PMID: 15834039
Peripheral neuropathy in CADASIL.	Sicurelli F	Journal of neurology	2005	PMID: 15827866
Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).	Lesnik Oberstein SA	Medicine	2003	PMID: 12861102
Cerebral microbleeds in CADASIL.	Lesnik Oberstein SA	Neurology	2001	PMID: 11571335
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Text-mined citations for rs1438626607 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000435.3(NOTCH3):c.3226C>T (p.Arg1076Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1438626607 ...