NM_005633.4(SOS1):c.806T>C (p.Met269Thr) AND Noonan syndrome 4

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000487454.5

Allele description [Variation Report for NM_005633.4(SOS1):c.806T>C (p.Met269Thr)]

NM_005633.4(SOS1):c.806T>C (p.Met269Thr)

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.806T>C (p.Met269Thr)

Other names:

p.M269T:ATG>ACG; NM_005633.3(SOS1):c.806T>C

HGVS:

NC_000002.12:g.39051202A>G
NG_007530.1:g.74262T>C
NM_001382394.1:c.785T>C
NM_001382395.1:c.806T>C
NM_005633.4:c.806T>CMANE SELECT
NP_001369323.1:p.Met262Thr
NP_001369324.1:p.Met269Thr
NP_005624.2:p.Met269Thr
NP_005624.2:p.Met269Thr
LRG_754t1:c.806T>C
LRG_754:g.74262T>C
LRG_754p1:p.Met269Thr
NC_000002.11:g.39278343A>G
NM_001382395.1:c.806T>C
NM_005633.3:c.806T>C
Q07889:p.Met269Thr
c.806T>C
p.Met259Thr

Protein change:

M262T

Links:

UniProtKB: Q07889#VAR_064504; dbSNP: rs137852813

NCBI 1000 Genomes Browser:

rs137852813

Molecular consequence:

NM_001382394.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001382395.1:c.806T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005633.4:c.806T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

Condition(s)

Name:: Noonan syndrome 4 (NS4)
Synonyms:: NOONAN SYNDROME WITH PIGMENTED VILLONODULAR SYNOVITIS; NL/MGCLS
Identifiers:: MONDO: MONDO:0012547; MedGen: C1853120; Orphanet: 648; OMIM: 610733

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000574532	GenePathDx, GenePath diagnostics	criteria provided, single submitter (GenePathDx_Criteria_classificationV2)	Pathogenic (Oct 1, 2016)	germline	clinical testing	GenePathDx_Criteria_classificationV2.doc, Citation Link,
SCV002318503	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20683980, 17586837, 19953625, 17143282, 25741868
SCV002564429	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000574532

GenePathDx, GenePath diagnostics

criteria provided, single submitter

(GenePathDx_Criteria_classificationV2)

Pathogenic
(Oct 1, 2016)

germline

clinical testing

GenePathDx_Criteria_classificationV2.doc,

Citation Link,

SCV002318503

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 22, 2022)

germline

clinical testing

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

SCV002564429

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 16, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	1	not provided	1	not provided	clinical testing

Citations

PubMed

Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations.

Longoni M, Moncini S, Cisternino M, Morella IM, Ferraiuolo S, Russo S, Mannarino S, Brazzelli V, Coi P, Zippel R, Venturin M, Riva P.

Am J Med Genet A. 2010 Sep;152A(9):2176-84. doi: 10.1002/ajmg.a.33564.

PubMed [citation]

PMID:: 20683980

SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.

Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, Doerr HG, Gaspar H, Hofbeck M, Gillessen-Kaesbach G, Koch A, Meinecke P, Mundlos S, Nowka A, Rauch A, Reif S, von Schnakenburg C, Seidel H, Wehner LE, Zweier C, Bauhuber S, Matejas V, et al.

J Med Genet. 2007 Oct;44(10):651-6. Epub 2007 Jun 23.

PubMed [citation]

PMID:: 17586837
PMCID:: PMC2597961

See all PubMed Citations (5)

Details of each submission

From GenePathDx, GenePath diagnostics, SCV000574532.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

Child with strong clinical suspicion of Noonan syndrome. Next generation DNA sequencing of peripheral blood sample has revealed the presence of a pathogenic variant NM_005633.3(SOS1):c.806T>C in the SOS1 gene in heterozygous state.

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

From 3billion, SCV002318503.1

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

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040662). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19953625, 17586837, 20683980, PS2_VS). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.895>=0.6, 3CNET: 0.892>=0.75). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012870,VCV000981559, PMID:17143282). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV002564429.1

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

Description

A heterozygous missense variation in exon 6 of the SOS1 gene (chr2:g.39051202A>C;) that result in the amino acid substitution of Arginine for Methionine at codon 269 (p.Met269Arg; ENST00000402219.8) was detected. thep.Met269Arg variant has not been reported in the 1000 genomes, gnomAD and our internal databases. the in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT AND Mutation Taster2. the reference codon is conserved across species.

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

Last Updated: May 12, 2024

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