VCV000134942.28 - ClinVar

NM_017617.5(NOTCH1):c.311A>G (p.Asn104Ser)

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.

(11)

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/Likely 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.311A>G (p.Asn104Ser)

Variation ID: 134942 Accession: VCV000134942.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 136523809 (GRCh38) [ NCBI UCSC ] 9: 139418261 (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	Jun 9, 2014	Oct 20, 2024	Jan 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_017617.5:c.311A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060087.3:p.Asn104Ser	missense
NM_017617.4:c.311A>G
NC_000009.12:g.136523809T>C
NC_000009.11:g.139418261T>C
NG_007458.1:g.26978A>G
LRG_1122:g.26978A>G
LRG_1122t1:c.311A>G	LRG_1122p1:p.Asn104Ser

... more HGVS ... less HGVS

Protein change

N104S

Other names

Canonical SPDI

NC_000009.12:136523808:T:C

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.

0.00020 (C)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039

Trans-Omics for Precision Medicine (TOPMed) 0.00054

The Genome Aggregation Database (gnomAD) 0.00056

Exome Aggregation Consortium (ExAC) 0.00094

The Genome Aggregation Database (gnomAD), exomes 0.00113

Links

ClinGen: CA161211 dbSNP: rs199654211 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	3494	3765

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	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 21, 2023	RCV000121692.10
Adams-Oliver syndrome 5	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV000228385.21
Connective tissue disorder	Likely benign (1)	criteria provided, single submitter	Nov 1, 2016	RCV000660138.8
Familial thoracic aortic aneurysm and aortic dissection	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Mar 27, 2018	RCV001170714.11
Aortic valve disease 1	Benign (1)	criteria provided, single submitter	Mar 15, 2022	RCV002269862.8
not provided	Likely benign (1)	criteria provided, single submitter	May 1, 2023	RCV003422001.10
NOTCH1-related disorder	Benign (1)	no assertion criteria provided	Dec 20, 2019	RCV004530026.2

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 benign (Jun 15, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000522067.4 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)
Likely benign (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782132.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Benign (Mar 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333315.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Benign (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adams-Oliver syndrome 5 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002555160.1 First in ClinVar: Jul 30, 2022 Last updated: Jul 30, 2022
Likely benign (Jul 21, 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: SCV004029542.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (12) PubMed: 24943832‚ 16614245‚ 21670202‚ 22210878‚ 19635999‚ 26837699‚ 23086750‚ 19245433‚ 22077063‚ 15472075‚ 23734977‚ 22858860
Likely benign (Jan 28, 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: SCV000290262.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aortic valve disease 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002555161.1 First in ClinVar: Jul 30, 2022 Last updated: Jul 30, 2022
Likely benign (Jan 09, 2018)	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: SCV000738425.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
Likely benign (May 01, 2023)	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: SCV004162065.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: NOTCH1: PP2, BS1 Number of individuals with the variant: 2
Benign (Dec 20, 2019)	no assertion criteria provided Method: clinical testing	NOTCH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004718784.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085890.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
click to load more click to collapse

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 likely 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
click to load more click to collapse

Text-mined citations for rs199654211 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_017617.5(NOTCH1):c.311A>G (p.Asn104Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199654211 ...