NM_006939.4(SOS2):c.800T>G (p.Met267Arg) AND Noonan syndrome 9

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 2, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000699741.4

Allele description [Variation Report for NM_006939.4(SOS2):c.800T>G (p.Met267Arg)]

NM_006939.4(SOS2):c.800T>G (p.Met267Arg)

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.800T>G (p.Met267Arg)
HGVS:
  • NC_000014.9:g.50182521A>C
  • NG_051073.1:g.54173T>G
  • NM_006939.4:c.800T>GMANE SELECT
  • NP_008870.2:p.Met267Arg
  • NC_000014.8:g.50649239A>C
  • NM_006939.2:c.800T>G
  • NM_006939.3:c.800T>G
Protein change:
M267R
Links:
dbSNP: rs797045167
NCBI 1000 Genomes Browser:
rs797045167
Molecular consequence:
  • NM_006939.4:c.800T>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

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
SCV000828465Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 20, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001366232Centre for Mendelian Genomics,University Medical Centre Ljubljanacriteria provided, single submitter
Pathogenic
(Mar 23, 2020)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001426179Department of Human Genetics, University Hospital Magdeburgcriteria provided, single submitter
Pathogenic
(Jul 2, 2020)
de novoclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes65not providednot providedyesclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, Majewski J, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR.

J Med Genet. 2015 Jun;52(6):413-21. doi: 10.1136/jmedgenet-2015-103018. Epub 2015 Mar 20.

PubMed [citation]
PMID:
25795793

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
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000828465.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces methionine with arginine at codon 267 of the SOS2 protein (p.Met267Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Noonan syndrome (PMID: 26173643) Experimental studies have shown that this missense change results in high levels of RAS, MEK, and ERK function, consistent with the known gain-of-function mechanism of disease (PMID: 26173643). The p.Met267 amino acid residue in SOS2 has been determined to be clinically significant (PMID: 25795793). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Centre for Mendelian Genomics,University Medical Centre Ljubljana, SCV001366232.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP3.

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

From Department of Human Genetics, University Hospital Magdeburg, SCV001426179.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providedyesclinical testing PubMed (2)

Description

This variant has been previously reported as pathogenic including well-established functional studies (PS1 and PS3). It is absent from gnomAD (PM2). Variants at the analogous position in SOS1 (c.806T>G and c.806T>C) have been classified as pathogenic (PM5_Strong). The REVEL score of this variant is 0.919 (PP3) and the variant has been classified as likely pathogenic in ClinVar (PP5).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot provided6not provided5not provided

Last Updated: Sep 29, 2021

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