NM_017617.5(NOTCH1):c.5542C>A (p.Leu1848Met) AND Aortic valve disease 1

Clinical significance:Uncertain significance (Last evaluated: Feb 27, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001353368.1

Allele description [Variation Report for NM_017617.5(NOTCH1):c.5542C>A (p.Leu1848Met)]

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

Gene:
NOTCH1:notch receptor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.3
Genomic location:
Preferred name:
NM_017617.5(NOTCH1):c.5542C>A (p.Leu1848Met)
HGVS:
  • NC_000009.12:g.136501844G>T
  • NG_007458.1:g.48943C>A
  • NM_017617.5:c.5542C>AMANE SELECT
  • NP_060087.3:p.Leu1848Met
  • LRG_1122t1:c.5542C>A
  • LRG_1122:g.48943C>A
  • LRG_1122p1:p.Leu1848Met
  • NC_000009.11:g.139396296G>T
Protein change:
L1848M
Molecular consequence:
  • NM_017617.5:c.5542C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Aortic valve disease 1 (AOVD1)
Identifiers:
MONDO: MONDO:0024523; MedGen: C3887892; OMIM: 109730

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001548526Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Uncertain significance
(Feb 27, 2021)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in NOTCH1 cause aortic valve disease.

Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D.

Nature. 2005 Sep 8;437(7056):270-4. Epub 2005 Jul 17.

PubMed [citation]
PMID:
16025100

NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.

McBride KL, Riley MF, Zender GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW, Cole SE.

Hum Mol Genet. 2008 Sep 15;17(18):2886-93. doi: 10.1093/hmg/ddn187. Epub 2008 Jun 30.

PubMed [citation]
PMID:
18593716
PMCID:
PMC2722892
See all PubMed Citations (6)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV001548526.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

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 in ClinVar nor the literature to our knowledge. Of three bioinformatics tools queried, two predict that p.Leu1848Met would be damaging, while another predicts that this substitution would be tolerated. The leucine residue at this position is strongly conserved across all vertebrate species assessed. This variant is not predicted to affect normal exon 30 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence, we consider the clinical significance of c.5542C>A to be uncertain at this time.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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