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.
ClinVar Genomic variation as it relates to human health
NM_017617.5(NOTCH1):c.4129C>T (p.Pro1377Ser)
Germline
Classification
Help
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.
(19)
Help
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
19
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.4129C>T (p.Pro1377Ser)
Variation ID: 134934 Accession: VCV000134934.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.3 9: 136505767 (GRCh38) [ NCBI UCSC ] 9: 139400219 (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 Apr 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_017617.5:c.4129C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060087.3:p.Pro1377Ser missense NM_017617.4:c.4129C>T NC_000009.12:g.136505767G>A NC_000009.11:g.139400219G>A NG_007458.1:g.45020C>T LRG_1122:g.45020C>T LRG_1122t1:c.4129C>T LRG_1122p1:p.Pro1377Ser - Protein change
- P1377S
- Other names
- -
- Canonical SPDI
- NC_000009.12:136505766:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00639 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00547
1000 Genomes Project 0.00639
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01700
The Genome Aggregation Database (gnomAD), exomes 0.01701
Exome Aggregation Consortium (ExAC) 0.01783
The Genome Aggregation Database (gnomAD) 0.01511
Trans-Omics for Precision Medicine (TOPMed) 0.01688
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
3477 | 3748 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (9) |
criteria provided, multiple submitters, no conflicts
|
Jul 21, 2023 | RCV000121684.22 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000230241.19 | |
| Benign (1) |
criteria provided, single submitter
|
Mar 15, 2022 | RCV002269859.8 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 7, 2022 | RCV002312813.10 | |
| Benign (1) |
criteria provided, single submitter
|
Nov 7, 2021 | RCV002505066.8 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Oct 24, 2023 | RCV002284189.10 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV003114267.18 |
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
(Aug 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000333221.4
First in ClinVar: Dec 06, 2016 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Adams-Oliver syndrome 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000290274.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Oct 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000527984.4
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
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic valve disease 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002554432.1
First in ClinVar: Jul 30, 2022 Last updated: Jul 30, 2022 |
|
|
|
Benign
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Adams-Oliver syndrome 5
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002554431.1
First in ClinVar: Jul 30, 2022 Last updated: Jul 30, 2022 |
|
|
|
Likely benign
(Jul 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029571.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
|
|
|
Benign
(Nov 07, 2022)
|
criteria provided, single submitter
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: SCV004239530.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Benign
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800246.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005041006.6
First in ClinVar: May 12, 2024 Last updated: Oct 20, 2024 |
Comment:
NOTCH1: BP4, BS1, BS2
Number of individuals with the variant: 1
|
|
|
Benign
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic valve disease 1
Adams-Oliver syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002806408.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Benign
(Feb 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000738330.5
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
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005323750.1
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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926993.1 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
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799686.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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: SCV002038489.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
|
|
|
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: SCV001809279.1 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
|
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: SCV001958687.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085882.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
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
|
|
|
Pathogenic
(Aug 25, 2022)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Myeloproliferative neoplasm, unclassifiable
Affected status: yes
Allele origin:
somatic
|
Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology
Accession: SCV002573650.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Number of individuals with the variant: 2
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
NOTCH1: BP4, BS1, BS2
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:
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:
NOTCH1: BP4, BS1, BS2
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.
Citations for germline classification of this variant
Help| 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 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs61751542 ...
HelpThese 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 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.