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

Clinical significance:Likely pathogenic (Last evaluated: Oct 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001264473.1

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]

Condition(s)

Name:
Rasopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: CN166718

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001442647Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Oct 19, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.

Cordeddu V, Yin JC, Gunnarsson C, Virtanen C, Drunat S, Lepri F, De Luca A, Rossi C, Ciolfi A, Pugh TJ, Bruselles A, Priest JR, Pennacchio LA, Lu Z, Danesh A, Quevedo R, Hamid A, Martinelli S, Pantaleoni F, Gnazzo M, Daniele P, Lissewski C, et al.

Hum Mutat. 2015 Nov;36(11):1080-7. doi: 10.1002/humu.22834. Epub 2015 Aug 3.

PubMed [citation]
PMID:
26173643
PMCID:
PMC4604019

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
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442647.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: SOS2 c.800T>G (p.Met267Arg) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes (gnomAD). c.800T>G has been reported in the literature in individuals affected with Noonan Syndrome (Cordeddu_2015, Bessis_2019). These data indicate that the variant may be associated with disease. In addition, another missense in the same residue (p.M267K) has been found in individuals affected with Noonan Syndrome suggesting this residue is clinical important (Yamamoto_2015, Ding_2019). At least one functional study reports this variant increases RAS and MEK/ERK activation (Cordeddu_2015). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Sep 29, 2021

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