ClinVar Genomic variation as it relates to human health
NM_006939.4(SOS2):c.800T>G (p.Met267Arg)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006939.4(SOS2):c.800T>G (p.Met267Arg)
Variation ID: 577079 Accession: VCV000577079.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q21.3 14: 50182521 (GRCh38) [ NCBI UCSC ] 14: 50649239 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 10, 2018 Mar 16, 2024 Nov 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006939.4:c.800T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008870.2:p.Met267Arg missense NC_000014.9:g.50182521A>C NC_000014.8:g.50649239A>C NG_051073.1:g.54173T>G - Protein change
- M267R
- Other names
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- Canonical SPDI
- NC_000014.9:50182520:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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SOS2 | - | - |
GRCh38 GRCh37 |
1486 | 1535 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Oct 17, 2022 | RCV001575734.5 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV000699741.10 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001251214.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2022 | RCV001264473.2 | |
SOS2-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV003411629.5 |
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. |
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Pathogenic
(Aug 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 9
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000828465.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met267 amino acid residue in SOS2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met267 amino acid residue in SOS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25795793). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOS2 function (PMID: 26173643). 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) performed at Invitae indicates that this missense variant is expected to disrupt SOS2 protein function. ClinVar contains an entry for this variant (Variation ID: 577079). This missense change has been observed in individuals with Noonan syndrome (PMID: 26173643; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 267 of the SOS2 protein (p.Met267Arg). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 9
Affected status: unknown
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002763113.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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SOS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108102.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The SOS2 c.800T>G variant is predicted to result in the amino acid substitution p.Met267Arg. This variant as been reported in multiple individuals with Noonan syndrome, … (more)
The SOS2 c.800T>G variant is predicted to result in the amino acid substitution p.Met267Arg. This variant as been reported in multiple individuals with Noonan syndrome, being documented as occurring de novo in at least one individual (Cordeddu et al. 2015. PubMed ID: 26173643; Lissewski et al. 2020. PubMed ID: 32788663). This variant has not been reported in a large population database, indicating this variant is rare. Alternative substitutions (Lys, Thr) at this amino acid position have also been reported as causative for Noonan syndrome (Yamamoto et al. 2015. PubMed ID: 25795793; Lissewski et al. 2021. PubMed ID: 32788663). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 9
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Department of Human Genetics, University Hospital Magdeburg
Accession: SCV001426179.1
First in ClinVar: Aug 02, 2020 Last updated: Aug 02, 2020 |
Comment:
This variant has been previously reported as pathogenic including well-established functional studies (PS1 and PS3). It is absent from gnomAD (PM2). Variants at the analogous … (more)
This variant has been previously reported as pathogenic including well-established functional studies (PS1 and PS3). It is absent from gnomAD (PM2). Variants at the analogous position in SOS1 (c.806T>G and c.806T>C) have been classified as pathogenic (PM5_Strong). The REVEL score of this variant is 0.919 (PP3) and the variant has been classified as likely pathogenic in ClinVar (PP5). (less)
Number of individuals with the variant: 6
Family history: yes
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Pathogenic
(Mar 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 9
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366232.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP3.
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Pathogenic
(Jun 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442647.2
First in ClinVar: Nov 12, 2020 Last updated: Aug 08, 2022 |
Comment:
Variant summary: SOS2 c.800T>G (p.Met267Arg) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. … (more)
Variant summary: SOS2 c.800T>G (p.Met267Arg) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes (gnomAD). c.800T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome (Cordeddu_2015, Bessis_2019, Lissewski_2021, Lallar_2021). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant increases RAS and MEK/ERK activation (Cordeddu_2015). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001802788.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate variant promotes enhanced phosphorylation of extracellular signal-regulated kinase (ERK) compared to wild type protein (Cordeddu et al., 2015); Not observed in … (more)
Published functional studies demonstrate variant promotes enhanced phosphorylation of extracellular signal-regulated kinase (ERK) compared to wild type protein (Cordeddu et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30707178, 26173643, 27942422, 29696775, 30417923, 32788663) (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
de novo
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Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001426700.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutation and Phenotypic Spectrum of Patients With RASopathies. | Lallar M | Indian pediatrics | 2021 | PMID: 33452774 |
Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications. | Lissewski C | European journal of human genetics : EJHG | 2021 | PMID: 32788663 |
A report on a girl of Noonan syndrome 9 presenting with bilateral lower limbs lymphedema. | Ding Y | Chinese medical journal | 2019 | PMID: 30707178 |
Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. | Bessis D | The British journal of dermatology | 2019 | PMID: 30417923 |
Expansion of the RASopathies. | Tidyman WE | Current genetic medicine reports | 2016 | PMID: 27942422 |
Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. | Cordeddu V | Human mutation | 2015 | PMID: 26173643 |
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. | Yamamoto GL | Journal of medical genetics | 2015 | PMID: 25795793 |
Text-mined citations for this variant ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.