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NM_017617.5(NOTCH1):c.5542C>A (p.Leu1848Met)

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Interpretation:
Uncertain significance​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
2 (Most recent: Apr 2, 2021)
Last evaluated:
Feb 27, 2021
Accession:
VCV001048775.1
Variation ID:
1048775
Description:
single nucleotide variant
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NM_017617.5(NOTCH1):c.5542C>A (p.Leu1848Met)

Allele ID
1036860
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
9q34.3
Genomic location
9: 136501844 (GRCh38) GRCh38 UCSC
9: 139396296 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000009.11:g.139396296G>T
NC_000009.12:g.136501844G>T
NG_007458.1:g.48943C>A
... more HGVS
Protein change
L1848M
Other names
-
Canonical SPDI
NC_000009.12:136501843:G:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Feb 27, 2021 RCV001353368.1
Uncertain significance 1 criteria provided, single submitter Apr 23, 2020 RCV001366341.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
NOTCH1 - - GRCh38
GRCh37
1772 1856

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Feb 27, 2021)
criteria provided, single submitter
Method: clinical testing
Aortic valve disease 1
Allele origin: germline
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001548526.1
Submitted: (Apr 02, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This NOTCH1 variant (rs35652719) is rare (<0.1%) in a large population dataset (gnomAD: 5/278682 total alleles, 0.002%, no homozygotes) and has not been reported previously … (more)
Uncertain significance
(Apr 23, 2020)
criteria provided, single submitter
Method: clinical testing
Adams-Oliver syndrome 5
Allele origin: germline
Invitae
Accession: SCV001562642.1
Submitted: (Jan 07, 2021)
Evidence details
Comment:
This sequence change replaces leucine with methionine at codon 1848 of the NOTCH1 protein (p.Leu1848Met). The leucine residue is highly conserved and there is a … (more)

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
Contribution of single-gene defects to congenital cardiac left-sided lesions in the prenatal setting. Sun H Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2020 PMID: 31633846
Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Kerstjens-Frederikse WS Genetics in medicine : official journal of the American College of Medical Genetics 2016 PMID: 26820064
Variants in the NOTCH1 gene in patients with aortic coarctation. Freylikhman O Congenital heart disease 2014 PMID: 24418111
NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. McBride KL Human molecular genetics 2008 PMID: 18593716
Mutations in NOTCH1 cause aortic valve disease. Garg V Nature 2005 PMID: 16025100

Record last updated Oct 08, 2021