VCV000286141.24 - ClinVar

NM_017617.5(NOTCH1):c.6555C>T (p.Asp2185=)

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.

(12)

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_017617.5(NOTCH1):c.6555C>T (p.Asp2185=)

Variation ID: 286141 Accession: VCV000286141.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 136497184 (GRCh38) [ NCBI UCSC ] 9: 139391636 (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	Mar 8, 2017	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_017617.5:c.6555C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060087.3:p.Asp2185=	synonymous
NM_017617.4:c.6555C>T
NC_000009.12:g.136497184G>A
NC_000009.11:g.139391636G>A
NG_007458.1:g.53603C>T
LRG_1122:g.53603C>T
LRG_1122t1:c.6555C>T	LRG_1122p1:p.Asp2185=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000009.12:136497183: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.

0.30491 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.58127

The Genome Aggregation Database (gnomAD) 0.58641

Trans-Omics for Precision Medicine (TOPMed) 0.60710

Exome Aggregation Consortium (ExAC) 0.61873

The Genome Aggregation Database (gnomAD), exomes 0.62193

1000 Genomes Project 30x 0.68957

1000 Genomes Project 0.69509

Links

ClinGen: CA5339874 dbSNP: rs2229974 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.
NOTCH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3487	3758

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 (6)	criteria provided, multiple submitters, no conflicts	Apr 4, 2023	RCV000313125.18
Aortic valve disease 1	Benign (2)	criteria provided, single submitter	Sep 5, 2021	RCV000607860.10
Adams-Oliver syndrome 5	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001519881.16
Familial thoracic aortic aneurysm and aortic dissection	Benign (1)	criteria provided, single submitter	Dec 30, 2014	RCV002314018.9
not provided	Benign (1)	criteria provided, single submitter	-	RCV004718165.1

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 (Sep 22, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000519072.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Feb 05, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339458.4 First in ClinVar: Dec 06, 2016 Last updated: Mar 08, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NOTCH1 Number of individuals with the variant: 31 Sex: mixed
Benign (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adams-Oliver syndrome 5 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002026837.1 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	Aortic valve disease 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002026838.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Benign (Apr 04, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003928454.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (12) PubMed: 24943832‚ 16614245‚ 21670202‚ 22210878‚ 19635999‚ 26837699‚ 23086750‚ 19245433‚ 22077063‚ 15472075‚ 23734977‚ 22858860
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Adams-Oliver syndrome 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001728841.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Dec 30, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000738279.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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: SCV005323727.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	Aortic valve disease 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734675.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
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: SCV001808413.1 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	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921195.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955695.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia.	Nadeu F	Blood	2016	PMID: 26837699
Recurrent mutations refine prognosis in chronic lymphocytic leukemia.	Baliakas P	Leukemia	2015	PMID: 24943832
NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients.	Willander K	BMC cancer	2013	PMID: 23734977
The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.	Oscier DG	Blood	2013	PMID: 23086750
Prognostic impact of δ-like ligand 4 and Notch1 in acute myeloid leukemia.	Zhang J	Oncology reports	2012	PMID: 22858860
Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma.	Kridel R	Blood	2012	PMID: 22210878
Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.	Rossi D	Blood	2012	PMID: 22077063
Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.	Fabbri G	The Journal of experimental medicine	2011	PMID: 21670202
Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol.	Mansour MR	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19635999
FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma.	Park MJ	British journal of haematology	2009	PMID: 19245433
Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia.	Breit S	Blood	2006	PMID: 16614245
Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.	Weng AP	Science (New York, N.Y.)	2004	PMID: 15472075
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NOTCH1	-	-	-	-
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Text-mined citations for rs2229974 ...

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_017617.5(NOTCH1):c.6555C>T (p.Asp2185=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2229974 ...