NM_005633.3(SOS1):c.1655G>C (p.Arg552Thr) AND Noonan syndrome 4

replaced

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 16, 2014
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000038523.2

Allele description

NM_005633.3(SOS1):c.1655G>C (p.Arg552Thr)

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.1655G>C (p.Arg552Thr)

HGVS:

NC_000002.12:g.39022773C>G
NG_007530.1:g.102691G>C
NM_005633.3:c.1655G>C
NP_005624.2:p.Arg552Thr
LRG_754t1:c.1655G>C
LRG_754:g.102691G>C
LRG_754p1:p.Arg552Thr
NC_000002.11:g.39249914C>G
c.1655G>C
p.R552T:AGG>ACG

Protein change:

R552T

Links:

dbSNP: rs397517154

NCBI 1000 Genomes Browser:

rs397517154

Molecular consequence:

NM_005633.3:c.1655G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Noonan syndrome 4 (NS4)
Synonyms:: NOONAN SYNDROME WITH PIGMENTED VILLONODULAR SYNOVITIS
Identifiers:: MedGen: C1853120; Orphanet: 648; OMIM: 610733
Age of onset:: Neonatal
Prevalence:: 6-9 / 10 000 648

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000062201	Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 16, 2014)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17143282, 19352411, 21387466, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000062201

Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jul 16, 2014)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, et al.

Nat Genet. 2007 Jan;39(1):75-9. Epub 2006 Dec 13. Erratum in: Nat Genet. 2007 Feb;39(2):276.

PubMed [citation]

PMID:: 17143282

SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions.

Beneteau C, Cavé H, Moncla A, Dorison N, Munnich A, Verloes A, Leheup B.

Eur J Hum Genet. 2009 Oct;17(10):1216-21. doi: 10.1038/ejhg.2009.44. Epub 2009 Apr 8.

PubMed [citation]

PMID:: 19352411
PMCID:: PMC2986637

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000062201.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (4)

Description

The Arg552Thr variant in SOS1 has been identified in at least 5 individuals with clinical features of Noonan syndrome (Beneteau 2009, Lepri 2011, LMM unpublished data) and was absent from large population studies. Arginine (Arg) at position 552 is highly conserved in mammals and evolutionarily distant species and other computational prediction tools suggest that this variant may impact the protein. Furthermore, several other amino acid changes at this position have been identified in individuals with Noonan syndrome (Arg552Ser, Arg552Lys, Arg552Met, Arg552Gly; Beneteau 2009, Lepri 2011), many of which occurred de novo, and functional studies showed that another variant at the same position (Arg552Gly) caused increased and prolonged RAS activation (Tartaglia 2007). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based on absence from controls and supporting functional evidence.

#	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		5	not provided	5	not provided

Last Updated: Mar 9, 2016

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