NM_017617.5(NOTCH1):c.839A>G (p.Asn280Ser) AND Adams-Oliver syndrome 5

Clinical significance:Uncertain significance (Last evaluated: Oct 1, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000471470.5

Allele description [Variation Report for NM_017617.5(NOTCH1):c.839A>G (p.Asn280Ser)]

NM_017617.5(NOTCH1):c.839A>G (p.Asn280Ser)

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.839A>G (p.Asn280Ser)
HGVS:
  • NC_000009.12:g.136519469T>C
  • NG_007458.1:g.31318A>G
  • NM_017617.5:c.839A>GMANE SELECT
  • NP_060087.3:p.Asn280Ser
  • LRG_1122t1:c.839A>G
  • LRG_1122:g.31318A>G
  • LRG_1122p1:p.Asn280Ser
  • NC_000009.11:g.139413921T>C
  • NM_017617.3:c.839A>G
Protein change:
N280S
Links:
dbSNP: rs367825691
NCBI 1000 Genomes Browser:
rs367825691
Molecular consequence:
  • NM_017617.5:c.839A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Adams-Oliver syndrome 5 (AOS5)
Identifiers:
MONDO: MONDO:0014459; MedGen: C4014970; Orphanet: 974; OMIM: 616028

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000548962Invitaecriteria provided, single submitter
Uncertain significance
(Oct 1, 2020)
germlineclinical testing

PubMed (2)
[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

Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.

Kerstjens-Frederikse WS, van de Laar IM, Vos YJ, Verhagen JM, Berger RM, Lichtenbelt KD, Klein Wassink-Ruiter JS, van der Zwaag PA, du Marchie Sarvaas GJ, Bergman KA, Bilardo CM, Roos-Hesselink JW, Janssen JH, Frohn-Mulder IM, van Spaendonck-Zwarts KY, van Melle JP, Hofstra RM, Wessels MW.

Genet Med. 2016 Sep;18(9):914-23. doi: 10.1038/gim.2015.193. Epub 2016 Jan 28.

PubMed [citation]
PMID:
26820064

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000548962.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces asparagine with serine at codon 280 of the NOTCH1 protein (p.Asn280Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in an individual affected with coarctation of the aorta (PMID: 26820064). ClinVar contains an entry for this variant (Variation ID: 409078). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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