NM_005633.3(SOS1):c.322G>A (p.Glu108Lys) AND Noonan syndrome

Clinical significance:Pathogenic (Last evaluated: Apr 3, 2017)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000038546.3

Allele description [Variation Report for NM_005633.3(SOS1):c.322G>A (p.Glu108Lys)]

NM_005633.3(SOS1):c.322G>A (p.Glu108Lys)

Gene:
SOS1:SOS Ras/Rac guanine nucleotide exchange factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p22.1
Genomic location:
Preferred name:
NM_005633.3(SOS1):c.322G>A (p.Glu108Lys)
Other names:
p.E108K:GAA>AAA; NM_005633.3(SOS1):c.322G>A
HGVS:
  • NC_000002.12:g.39058696C>T
  • NG_007530.1:g.66768G>A
  • NM_005633.3:c.322G>A
  • NP_005624.2:p.Glu108Lys
  • LRG_754t1:c.322G>A
  • LRG_754:g.66768G>A
  • LRG_754p1:p.Glu108Lys
  • NC_000002.11:g.39285837C>T
  • Q07889:p.Glu108Lys
  • c.322G>A
Protein change:
E108K
Links:
UniProtKB: Q07889#VAR_030423; dbSNP: rs397517164
NCBI 1000 Genomes Browser:
rs397517164
Molecular consequence:
  • NM_005633.3:c.322G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Noonan syndrome (NS)
Synonyms:
Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:
MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000062224Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Dec 17, 2013)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000616437ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Apr 3, 2017)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided32not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.

Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, et al.

Hum Mutat. 2011 Jul;32(7):760-72. doi: 10.1002/humu.21492. Epub 2011 Apr 28.

PubMed [citation]
PMID:
21387466
PMCID:
PMC3118925

Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless.

Gureasko J, Kuchment O, Makino DL, Sondermann H, Bar-Sagi D, Kuriyan J.

Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3430-5. doi: 10.1073/pnas.0913915107. Epub 2010 Feb 4.

PubMed [citation]
PMID:
20133692
PMCID:
PMC2816639
See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000062224.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (8)

Description

The Glu108Lys variant in SOS1 has been reported in 6 individuals with clinical f eatures of Noonan syndrome and segregated with disease in 1 affected relative (T artaglia 2007, Lepri 2011, LMM unpublished data). This variant has not been iden tified in large population studies. Functional studies have shown that the Glu10 8Lys variant leads to increased activation of SOS1 protein (Gureasko 2010, Smith 2013, Saliba 2013, Findlay 2013). However, these in vitro assays may not accura tely represent biological function. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not provided2not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616437.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2). The p.Glu108Lys variant has been identified in several independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2; PMID: 17143282; 23487764). In vitro functional studies provide some evidence that the p.Glu108Lys variant may impact protein function (PS3; PMID: 17143282, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS3, PM6, PS4_Moderate, PM2, PP2.

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

Last Updated: Sep 6, 2021

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