ClinVar Genomic variation as it relates to human health
NM_006939.4(SOS2):c.791C>A (p.Thr264Lys)
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.791C>A (p.Thr264Lys)
Variation ID: 684626 Accession: VCV000684626.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q21.3 14: 50182530 (GRCh38) [ NCBI UCSC ] 14: 50649248 (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 Aug 31, 2019 Feb 14, 2024 Feb 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006939.4:c.791C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008870.2:p.Thr264Lys missense NC_000014.9:g.50182530G>T NC_000014.8:g.50649248G>T NG_051073.1:g.54164C>A - Protein change
- T264K
- Other names
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- Canonical SPDI
- NC_000014.9:50182529:G:T
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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
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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
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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/Likely pathogenic (2) |
no assertion criteria provided
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Aug 3, 2015 | RCV000845124.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 23, 2020 | RCV001269182.1 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2023 | RCV001250766.4 |
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
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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
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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
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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
(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: SCV001426177.1
First in ClinVar: Aug 02, 2020 Last updated: Aug 02, 2020 |
Comment:
This variant has been previously reported as pathogenic (PS1). It is absent from gnomAD (PM2). The variant is assumed to be de novo, but without … (more)
This variant has been previously reported as pathogenic (PS1). It is absent from gnomAD (PM2). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6). The REVEL Score of this variant is 0.713 (PP3) and the variant has been cllassified as likely pathogenic in ClinVar (PP5). (less)
Number of individuals with the variant: 1
Family history: yes
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Likely pathogenic
(Nov 23, 2020)
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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: SCV001448466.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Comment:
Variant summary: SOS2 c.791C>A (p.Thr264Lys) results in a non-conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain (IPR001895) of the encoded … (more)
Variant summary: SOS2 c.791C>A (p.Thr264Lys) results in a non-conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain (IPR001895) 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 251280 control chromosomes (gnomAD). c.791C>A has been reported in the literature in individuals affected with Noonan Syndrome (Cordeddu_2015, Lissewski_2020). These data indicate that the variant may be associated with disease. Variant was functionally assessed in vitro using HEK293 cells and resulted in higher levels of GTP-bound RAS and increased signaling of Ras/MAPK pathway consistent with the known molecular mechanism of disease (Cordeddu_2015, Tidyman_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (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: SCV002763116.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Dec 29, 2022)
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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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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920500.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
This variant has been reported in the literature as de novo in at least 2 individuals with clinical suspicion or diagnoses of Noonan syndrome (Cordeddu … (more)
This variant has been reported in the literature as de novo in at least 2 individuals with clinical suspicion or diagnoses of Noonan syndrome (Cordeddu 2015 PMID: 26173643; Lissewski 2021 PMID: 32788663); multiple laboratories in ClinVar have also reportedly identified it as de novo in affected individuals (Variation ID: 684626). This variant is not present in gnomAD. An in vitro functional study demonstrated that this variant results in both higher levels of GTP-bound Ras protein as well as increased signaling of the Ras/MAPK pathway; these findings are consistent with the gain-of-function mechanism associated with the SOS2 gene and Noonan syndrome (Cordeddu 2015 PMID: 26173643; Tidyman 2016 PMID: 27942422). Another variant at this amino acid position (p.Thr264Arg) is pathogenic, and the p.Thr264 residue has been referred to as a mutational "hotspot" (Lissewski 2021 PMID: 32788663). Additionally, the same variant at the corresponding amino acid position in the highly homologous SOS1 gene (p.Thr266Lys) is a well-established pathogenic variant, suggesting that this variant in the SOS2 gene may be similarly deleterious (Roberts 2007 PMID: 17143285; Lissewski 2021 PMID: 32788663). Finally, evolutionary conservation and computational prediction tools support that this variant likely impacts the protein. In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(Feb 16, 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: SCV004297089.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 264 of the SOS2 protein (p.Thr264Lys). … (more)
This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 264 of the SOS2 protein (p.Thr264Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26173643, 32788663). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 684626). 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 SOS2 protein function. Experimental studies have shown that this missense change affects SOS2 function (PMID: 26173643). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 03, 2015)
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no assertion criteria provided
Method: literature only
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Noonan syndrome
Affected status: yes
Allele origin:
de novo
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Yale Center for Mendelian Genomics, Yale University
Accession: SCV000987060.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
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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: SCV001426698.1
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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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 |
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 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 20, 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.