VCV000256129.32 - ClinVar

NM_000435.3(NOTCH3):c.2538C>T (p.Cys846=)

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.

(13)

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.

Benign

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.2538C>T (p.Cys846=)

Variation ID: 256129 Accession: VCV000256129.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.12 19: 15184323 (GRCh38) [ NCBI UCSC ] 19: 15295134 (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	Oct 3, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000435.3:c.2538C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000426.2:p.Cys846=	synonymous
NC_000019.10:g.15184323G>A
NC_000019.9:g.15295134G>A
NG_009819.1:g.21659C>T

Protein change

Other names

Canonical SPDI

NC_000019.10:15184322: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.

0.48003 (G)

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

1000 Genomes Project 30x 0.51562

1000 Genomes Project 0.51997

Trans-Omics for Precision Medicine (TOPMed) 0.54058

The Genome Aggregation Database (gnomAD) 0.56438

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.56643

The Genome Aggregation Database (gnomAD), exomes 0.64094

Exome Aggregation Consortium (ExAC) 0.64274

Links

ClinGen: CA9263344 dbSNP: rs1043996 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 specified	Benign (4)	criteria provided, single submitter	-	RCV000241854.19
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (4)	criteria provided, multiple submitters, no conflicts	Sep 5, 2021	RCV000269025.17
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001521143.23
Lateral meningocele syndrome	Benign (1)	criteria provided, single submitter	Sep 5, 2021	RCV001785529.10

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304251.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
Benign (May 17, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000677222.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 24086431
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000410992.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 01, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001827691.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Benign (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002026910.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Benign (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lateral meningocele syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002026911.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Benign (Jan 14, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157012.3 First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022
Benign (Feb 01, 2024)	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: SCV001730418.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005308379.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001806965.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744534.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967517.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: phenotyping only	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Affected status: unknown Allele origin: unknown	GenomeConnect - CureCADASIL Accession: SCV001245244.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020	Comment: Variant interpreted as Benign and reported on 06-21-2005 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Benign and reported on 06-21-2005 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Hypermetropia (present) , Abnormality of the lens (present) , Myopia (disease) (present) , Hypercholesterolemia (present) , Stroke (present) , Abnormality of the musculature of the … (more) Hypermetropia (present) , Abnormality of the lens (present) , Myopia (disease) (present) , Hypercholesterolemia (present) , Stroke (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Morphological abnormality of the central nervous system (present) , Cognitive impairment (present) , Encephalopathy (present) , Memory impairment (present) , Anxiety (present) , Depressivity (present) , Hallucinations (present) (less) Age: 50-59 years Sex: male Testing laboratory: Athena Diagnostics Inc Date variant was reported to submitter: 2005-06-21 Testing laboratory interpretation: Benign
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant interpreted as Benign and reported on 06-21-2005 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.

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
NOTCH3 variants and risk of ischemic stroke.	Ross OA	PloS one	2013	PMID: 24086431

Text-mined citations for rs1043996 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000435.3(NOTCH3):c.2538C>T (p.Cys846=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1043996 ...