NM_005633.4(SOS1):c.1867T>A (p.Phe623Ile) AND Noonan syndrome and Noonan-related syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 28, 2019
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:: RCV000788001.4

Allele description [Variation Report for NM_005633.4(SOS1):c.1867T>A (p.Phe623Ile)]

NM_005633.4(SOS1):c.1867T>A (p.Phe623Ile)

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.1867T>A (p.Phe623Ile)

HGVS:

NC_000002.12:g.39014838A>T
NG_007530.1:g.110626T>A
NM_001382394.1:c.1846T>A
NM_001382395.1:c.1867T>A
NM_005633.4:c.1867T>AMANE SELECT
NP_001369323.1:p.Phe616Ile
NP_001369324.1:p.Phe623Ile
NP_005624.2:p.Phe623Ile
NP_005624.2:p.Phe623Ile
LRG_754t1:c.1867T>A
LRG_754:g.110626T>A
LRG_754p1:p.Phe623Ile
NC_000002.11:g.39241979A>T
NM_005633.3:c.1867T>A

Protein change:

F616I

Links:

dbSNP: rs727505093

NCBI 1000 Genomes Browser:

rs727505093

Molecular consequence:

NM_001382394.1:c.1846T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382395.1:c.1867T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005633.4:c.1867T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome and Noonan-related syndrome
Identifiers:: MONDO: MONDO:0020297; MedGen: C5681679; Orphanet: 98733

Recent activity

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RecName: Full=Spindle and centriole-associated protein 1; AltName: Full=Coiled-c...
RecName: Full=Spindle and centriole-associated protein 1; AltName: Full=Coiled-coil domain-containing protein 52
gi|143955295|sp|Q8C804.2|SPICE_MOUS

Protein
Danio rerio zgc:162648, mRNA (cDNA clone MGC:162648 IMAGE:7165849), complete cds
Danio rerio zgc:162648, mRNA (cDNA clone MGC:162648 IMAGE:7165849), complete cds
gi|134024884|gb|BC135040.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000927033	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Likely pathogenic (Feb 28, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 17586837, 20673819 Citation Link,
SCV002060850	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 13, 2020)	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

SCV000927033

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Likely pathogenic
(Feb 28, 2019)

germline

curation

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

Citation Link,

SCV002060850

Genome Diagnostics Laboratory, The Hospital for Sick Children

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 13, 2020)

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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

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

Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I.

Fabretto A, Kutsche K, Harmsen MB, Demarini S, Gasparini P, Fertz MC, Zenker M.

Eur J Med Genet. 2010 Sep-Oct;53(5):322-4. doi: 10.1016/j.ejmg.2010.07.011. Epub 2010 Jul 29.

PubMed [citation]

PMID:: 20673819

See all PubMed Citations (3)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927033.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The c.1867T>A (p.Phe623Ile) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of Noonan syndrome (PS2; PMID 17586837, 20673819). The p.Phe623Ile variant has also been identified in another independent occurrence in a patient with clinical features of Noonan syndrome (PS4_Supporting; PMID 20673819). This variant was absent from large population studies (PM2; gnomAD; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Phe623Ile variant may impact the protein (PP3). 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). Of note, two different pathogenic missense variants have been previously reported at this codon of SOS1 (p.Phe623Val and p.Phe623Glu) which may indicate that this residue is critical to the function of the protein, however these variants have not yet met the criteria to be classified as pathogenic (PM5 not met). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM2, PP2, PP3.

#	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

From Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV002060850.1

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

#	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: Nov 4, 2023

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