VCV000981586.8 - ClinVar

NM_005633.4(SOS1):c.2708A>C (p.Glu903Ala)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

3 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005633.4(SOS1):c.2708A>C (p.Glu903Ala)

Variation ID: 981586 Accession: VCV000981586.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p22.1 2: 39006495 (GRCh38) [ NCBI UCSC ] 2: 39233636 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 23, 2020	Feb 25, 2025	Nov 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005633.4:c.2708A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005624.2:p.Glu903Ala	missense
NM_001382394.1:c.2687A>C	NP_001369323.1:p.Glu896Ala	missense
NM_001382395.1:c.2708A>C	NP_001369324.1:p.Glu903Ala	missense
NC_000002.12:g.39006495T>G
NC_000002.11:g.39233636T>G
NG_007530.1:g.118969A>C
LRG_754:g.118969A>C
LRG_754t1:c.2708A>C

... more HGVS ... less HGVS

Protein change

E896A, E903A

Other names

Canonical SPDI

NC_000002.12:39006494:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA346363209 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SOS1		No evidence available	No evidence available	GRCh38 GRCh37	1883	2005

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Noonan syndrome	Uncertain significance (1)	no assertion criteria provided	-	RCV001261112.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Oct 8, 2024	RCV002436981.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 19, 2022	RCV002469364.1
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Nov 27, 2024	RCV002537613.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Nov 19, 2022) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002766299.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022
Uncertain significance (Oct 08, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002744975.3 First in ClinVar: Nov 29, 2022 Last updated: Jan 13, 2025	Comment: The c.2708A>C (p.E903A) alteration is located in exon 17 (coding exon 17) of the SOS1 gene. This alteration results from a A to C substitution … (more) The c.2708A>C (p.E903A) alteration is located in exon 17 (coding exon 17) of the SOS1 gene. This alteration results from a A to C substitution at nucleotide position 2708, causing the glutamic acid (E) at amino acid position 903 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Nov 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003468067.3 First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 903 of the SOS1 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 903 of the SOS1 protein (p.Glu903Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 981586). Invitae Evidence 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 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. 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. (less)
Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Noonan syndrome Affected status: yes Allele origin: unknown	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001438519.1 First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020

Comment:

The c.2708A>C (p.E903A) alteration is located in exon 17 (coding exon 17) of the SOS1 gene. This alteration results from a A to C substitution at nucleotide position 2708, causing the glutamic acid (E) at amino acid position 903 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 903 of the SOS1 protein (p.Glu903Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 981586). Invitae Evidence 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 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. 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_005633.4(SOS1):c.2708A>C (p.Glu903Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...