NM_005633.4(SOS1):c.1642A>C (p.Ser548Arg) AND Noonan syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000038515.16

Allele description [Variation Report for NM_005633.4(SOS1):c.1642A>C (p.Ser548Arg)]

NM_005633.4(SOS1):c.1642A>C (p.Ser548Arg)

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_005633.4(SOS1):c.1642A>C (p.Ser548Arg)

Other names:

p.S548R:AGT>CGT; NM_005633.3(SOS1):c.1642A>C

HGVS:

NC_000002.12:g.39022786T>G
NG_007530.1:g.102678A>C
NM_001382394.1:c.1621A>C
NM_001382395.1:c.1642A>C
NM_005633.4:c.1642A>CMANE SELECT
NP_001369323.1:p.Ser541Arg
NP_001369324.1:p.Ser548Arg
NP_005624.2:p.Ser548Arg
NP_005624.2:p.Ser548Arg
NP_005624.2:p.Ser548Arg
LRG_754t1:c.1642A>C
LRG_754:g.102678A>C
LRG_754p1:p.Ser548Arg
NC_000002.11:g.39249927T>G
NM_005633.3:c.1642A>C
Q07889:p.Ser548Arg
c.1642A>C

Protein change:

S541R

Links:

UniProtKB: Q07889#VAR_030432; dbSNP: rs397517149

NCBI 1000 Genomes Browser:

rs397517149

Molecular consequence:

NM_001382394.1:c.1621A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001382395.1:c.1642A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005633.4:c.1642A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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B4GALNT3 [Gracilinanus agilis]
B4GALNT3 [Gracilinanus agilis]
Gene ID:123248876

Gene
LOC4341642 [Oryza sativa Japonica Group]
LOC4341642 [Oryza sativa Japonica Group]
Gene ID:4341642

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000062193	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Oct 28, 2006)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17143282, 17143285, 23487764, 21387466, 24033266
SCV000616385	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Apr 3, 2017)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 29493581, 17143282, 17143285 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000062193

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Oct 28, 2006)

germline

clinical testing

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

SCV000616385

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Apr 3, 2017)

germline

curation

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	8	7	not provided	not provided	not provided	clinical testing

Citations

PubMed

NMR-based functional profiling of RASopathies and oncogenic RAS mutations.

Smith MJ, Neel BG, Ikura M.

Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9. doi: 10.1073/pnas.1218173110. Epub 2013 Mar 4.

PubMed [citation]

PMID:: 23487764
PMCID:: PMC3607025

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

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000062193.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Ser548Arg variant in SOS1 has been reported in >10 individuals with clinic al features of Noonan syndrome and was de novo in at least 2 of these individual s (Tartaglia 2007, Roberts 2007, Lepri 2011, LMM unpublished data). It was absen t from large population studies. In vitro functional studies provide some eviden ce that the p.Ser548Arg variant may impact protein function (Smith et al., 2013) . In summary, this variant meets our criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		8	not provided	7	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616385.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PS3 PS2_VeryStrong.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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