NM_005633.4(SOS1):c.2122G>A (p.Ala708Thr) AND Joubert syndrome 3

Germline classification:: Benign (1 submission)
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:: RCV001258236.10

Allele description [Variation Report for NM_005633.4(SOS1):c.2122G>A (p.Ala708Thr)]

NM_005633.4(SOS1):c.2122G>A (p.Ala708Thr)

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.2122G>A (p.Ala708Thr)

Other names:

NM_005633.3(SOS1):c.2122G>A

HGVS:

NC_000002.12:g.39013505C>T
NG_007530.1:g.111959G>A
NM_001382394.1:c.2101G>A
NM_001382395.1:c.2122G>A
NM_005633.4:c.2122G>AMANE SELECT
NP_001369323.1:p.Ala701Thr
NP_001369324.1:p.Ala708Thr
NP_005624.2:p.Ala708Thr
NP_005624.2:p.Ala708Thr
LRG_754t1:c.2122G>A
LRG_754:g.111959G>A
LRG_754p1:p.Ala708Thr
NC_000002.11:g.39240646C>T
NM_005633.3:c.2122G>A
Q07889:p.Ala708Thr
c.2122G>A

Protein change:

A701T

Links:

UniProtKB: Q07889#VAR_066053; dbSNP: rs140811086

NCBI 1000 Genomes Browser:

rs140811086

Molecular consequence:

NM_001382394.1:c.2101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382395.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005633.4:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Joubert syndrome 3 (JBTS3)
Synonyms:: Joubert syndrome with ocular anomalies; AHI1-related Ciliopathy
Identifiers:: MONDO: MONDO:0012078; MedGen: C1837713; Orphanet: 220493; OMIM: 608629

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001435142	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	research	PubMed (3) [See all records that cite these PMIDs] 22585553, 21340158, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001435142

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign

germline

research

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1.

Fahrner JA, Frazier A, Bachir S, Walsh MF, Applegate CD, Thompson R, Halushka MK, Murphy AM, Gunay-Aygun M.

Am J Med Genet A. 2012 Jun;158A(6):1414-21. doi: 10.1002/ajmg.a.35363. Epub 2012 May 14.

PubMed [citation]

PMID:: 22585553
PMCID:: PMC5101836

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil AS, Malaquias AC, Wanderley LT, Kim CA, Krieger JE, Jorge AA, Pereira AC, Bertola DR.

Arq Bras Endocrinol Metabol. 2010 Nov;54(8):717-22.

PubMed [citation]

PMID:: 21340158

See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001435142.1

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

Description

The heterozygous p.Ala708Thr variant in SOS1 has only been previously reported in individuals without Noonan syndrome but has been reported in association with Noonan syndrome (PMID: 22585553, 21340158), and has been identified in >5% of Latino chromosomes and 23 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant Noonan syndrome.

#	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: Feb 25, 2025

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