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NM_005633.4(SOS1):c.1352C>G (p.Thr451Arg) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 23, 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:
RCV000587209.5

Allele description [Variation Report for NM_005633.4(SOS1):c.1352C>G (p.Thr451Arg)]

NM_005633.4(SOS1):c.1352C>G (p.Thr451Arg)

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.1352C>G (p.Thr451Arg)
HGVS:
  • NC_000002.12:g.39023076G>C
  • NG_007530.1:g.102388C>G
  • NM_001382394.1:c.1331C>G
  • NM_001382395.1:c.1352C>G
  • NM_005633.4:c.1352C>GMANE SELECT
  • NP_001369323.1:p.Thr444Arg
  • NP_001369324.1:p.Thr451Arg
  • NP_005624.2:p.Thr451Arg
  • NP_005624.2:p.Thr451Arg
  • LRG_754t1:c.1352C>G
  • LRG_754:g.102388C>G
  • LRG_754p1:p.Thr451Arg
  • NC_000002.11:g.39250217G>C
  • NM_005633.3:c.1352C>G
Protein change:
T444R
Links:
dbSNP: rs730880218
NCBI 1000 Genomes Browser:
rs730880218
Molecular consequence:
  • NM_001382394.1:c.1331C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001382395.1:c.1352C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005633.4:c.1352C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000330770GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Uncertain significance
(Oct 23, 2023) 		germlineclinical testing

Citation Link,

SCV000698612Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Dec 24, 2016) 		germlineclinical testing

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000330770.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Identified in a postnatal sample sent for Noonan syndrome testing in published literature; clinical information was not provided (Leach et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30050098, 29907801, 20648242, 29493581, 17143282, 21387466, 12628188)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698612.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: The c.1352C>G (p.Thr451Arg) in SOS1 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located within Pleckstrin homology (PH) domain functional domain that is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.000008 (1/121314 chrs tested), exclusively in individuals of Latino origin (0.00008; 1/11576 chrs tested). The latter frequency exceeds the estimated maximal expected allele frequency of a pathogenic variant in SOS1 gene (0.00003). The variant is present in a control population dataset of gmomAD exclusively in individuals of Latino origin: 0.000196 (7/35710chrs), suggesting that it may be a rare ethnic-specific functional polymorphism. However, since the data set is still in beta mode, this data was not captured in pbGP. The variant has not, to our knowledge, been identified in patients with NSRD via published reports but was cited as VUS by a reputable database/diagnostic laboratory. At this time there is not sufficient evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 16, 2025