NM_005633.4(SOS1):c.3412A>G (p.Ile1138Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 3, 2023
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:: RCV000587119.17

Allele description [Variation Report for NM_005633.4(SOS1):c.3412A>G (p.Ile1138Val)]

NM_005633.4(SOS1):c.3412A>G (p.Ile1138Val)

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.3412A>G (p.Ile1138Val)

Other names:

p.I1138V:ATA>GTA

HGVS:

NC_000002.12:g.38987571T>C
NG_007530.1:g.137893A>G
NM_001382394.1:c.3391A>G
NM_001382395.1:c.3367A>G
NM_005633.4:c.3412A>GMANE SELECT
NP_001369323.1:p.Ile1131Val
NP_001369324.1:p.Ile1123Val
NP_005624.2:p.Ile1138Val
NP_005624.2:p.Ile1138Val
LRG_754t1:c.3412A>G
LRG_754:g.137893A>G
LRG_754p1:p.Ile1138Val
NC_000002.11:g.39214712T>C
NM_005633.3:c.3412A>G

Protein change:

I1123V

Links:

dbSNP: rs56248239

NCBI 1000 Genomes Browser:

rs56248239

Molecular consequence:

NM_001382394.1:c.3391A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001382395.1:c.3367A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005633.4:c.3412A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209085	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jul 25, 2018)	germline	clinical testing	Citation Link,
SCV002049617	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Nov 3, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000209085

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jul 25, 2018)

germline

clinical testing

Citation Link,

SCV002049617

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain significance
(Nov 3, 2023)

germline

clinical testing

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	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000209085.13

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

Description

The c.3412 A>G (I1138V ) variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/268,480 global alleles (0.003%) in large population cohorts (Lek et al., 2016). Multiple in silico splice prediction programs predict that the c.3412 A>G substitution creates a cryptic splice donor site upstream of the canonical splice donor site in intron 22, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the actual effect of this sequence change in this individual is unknown.If expressed and translated, the I1138V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.

#	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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049617.2

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

#	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: Feb 25, 2025

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