NM_005633.4(SOS1):c.1426G>T (p.Gly476Trp) AND RASopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 10, 2022
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:: RCV003655696.2

Allele description [Variation Report for NM_005633.4(SOS1):c.1426G>T (p.Gly476Trp)]

NM_005633.4(SOS1):c.1426G>T (p.Gly476Trp)

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.1426G>T (p.Gly476Trp)

HGVS:

NC_000002.12:g.39023002C>A
NG_007530.1:g.102462G>T
NM_001382394.1:c.1405G>T
NM_001382395.1:c.1426G>T
NM_005633.4:c.1426G>TMANE SELECT
NP_001369323.1:p.Gly469Trp
NP_001369324.1:p.Gly476Trp
NP_005624.2:p.Gly476Trp
NP_005624.2:p.Gly476Trp
LRG_754t1:c.1426G>T
LRG_754:g.102462G>T
LRG_754p1:p.Gly476Trp
NC_000002.11:g.39250143C>A
NM_005633.3:c.1426G>T

Protein change:

G469W

Molecular consequence:

NM_001382394.1:c.1405G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001382395.1:c.1426G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005633.4:c.1426G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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Mus musculus
Mus musculus
Unraveling the Sox4-orchestrated pro-B cell differentiation program: Intricate roles of the RAG and CK1ε genes (ChIP-Seq)

BioProject
Sulfurovum sp. AR strain:AR
Sulfurovum sp. AR strain:AR
Draft genome sequence of Sulfurovum sp. strain AR

BioProject
iso glutaminyl cyclase, isoform B [Drosophila melanogaster]
iso glutaminyl cyclase, isoform B [Drosophila melanogaster]
gi|28574640|ref|NP_788550.1|

Protein
Homo sapiens sulfide quinone reductase-like (yeast), mRNA (cDNA clone MGC:10012 ...
Homo sapiens sulfide quinone reductase-like (yeast), mRNA (cDNA clone MGC:10012 IMAGE:3884024), complete cds
gi|16877129|gb|BC016836.1|

Nucleotide
htpX [Burkholderia cepacia]
htpX [Burkholderia cepacia]
Gene ID:56663163

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004410168	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 10, 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

SCV004410168

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 10, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004410168.1

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 476 of the SOS1 protein (p.Gly476Trp).

#	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: Sep 29, 2024

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