NM_006939.4(SOS2):c.2600A>G (p.Asn867Ser) AND Noonan syndrome 9

Clinical significance:Uncertain significance (Last evaluated: Apr 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:
RCV000792762.3

Allele description [Variation Report for NM_006939.4(SOS2):c.2600A>G (p.Asn867Ser)]

NM_006939.4(SOS2):c.2600A>G (p.Asn867Ser)

Gene:
SOS2:SOS Ras/Rho guanine nucleotide exchange factor 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q21.3
Genomic location:
Preferred name:
NM_006939.4(SOS2):c.2600A>G (p.Asn867Ser)
HGVS:
  • NC_000014.9:g.50145237T>C
  • NG_051073.1:g.91457A>G
  • NM_006939.4:c.2600A>GMANE SELECT
  • NP_008870.2:p.Asn867Ser
  • NC_000014.8:g.50611955T>C
  • NM_006939.2:c.2600A>G
Protein change:
N867S
Links:
dbSNP: rs561495878
NCBI 1000 Genomes Browser:
rs561495878
Molecular consequence:
  • NM_006939.4:c.2600A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Noonan syndrome 9 (NS9)
Identifiers:
MONDO: MONDO:0014691; MedGen: C4225282; Orphanet: 648; OMIM: 616559

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000932079Invitaecriteria provided, single submitter
Uncertain significance
(Apr 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

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186

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, SCV000932079.3

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

Description

This sequence change replaces asparagine with serine at codon 867 of the SOS2 protein (p.Asn867Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs561495878, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SOS2-related disease. ClinVar contains an entry for this variant (Variation ID: 506639). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant 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: Oct 7, 2021

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