ClinVar Genomic variation as it relates to human health
NM_005633.4(SOS1):c.322G>A (p.Glu108Lys)
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_005633.4(SOS1):c.322G>A (p.Glu108Lys)
Variation ID: 40649 Accession: VCV000040649.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.1 2: 39058696 (GRCh38) [ NCBI UCSC ] 2: 39285837 (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 Dec 19, 2017 Feb 20, 2024 Apr 3, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005633.4:c.322G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005624.2:p.Glu108Lys missense NM_001382394.1:c.301G>A NP_001369323.1:p.Glu101Lys missense NM_001382395.1:c.322G>A NP_001369324.1:p.Glu108Lys missense NC_000002.12:g.39058696C>T NC_000002.11:g.39285837C>T NG_007530.1:g.66768G>A LRG_754:g.66768G>A LRG_754t1:c.322G>A LRG_754p1:p.Glu108Lys Q07889:p.Glu108Lys - Protein change
- E108K, E101K
- Other names
- p.E108K:GAA>AAA
- NM_005633.3(SOS1):c.322G>A
- Canonical SPDI
- NC_000002.12:39058695:C: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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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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SOS1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1591 | 1691 |
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
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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 (2) |
reviewed by expert panel
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Apr 3, 2017 | RCV000038546.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2017 | RCV000159144.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2023 | RCV000537356.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2020 | RCV001813280.3 |
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
(Apr 03, 2017)
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reviewed by expert panel
Method: curation
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV000616437.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; … (more)
The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2). The p.Glu108Lys variant has been identified in several independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2; PMID: 17143282; 23487764). In vitro functional studies provide some evidence that the p.Glu108Lys variant may impact protein function (PS3; PMID: 17143282, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS3, PM6, PS4_Moderate, PM2, PP2. (less)
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Pathogenic
(Jan 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060951.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
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Pathogenic
(Aug 10, 2017)
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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: SCV000209088.10
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
The E108K pathogenic variant in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007; Lepri et al., 2011). … (more)
The E108K pathogenic variant in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007; Lepri et al., 2011). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where amino acids with similar properties to Glutamic Acid are tolerated across species. However, the E108K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, functional studies demonstrate that the E108K variant, which is located in the histone fold domain of the encoded protein, disrupts protein activation and membrane assocation (Gureasko et al., 2010; Saliba et al., 2014). We interpret E108K as a pathogenic variant, consistent with global developmental delay, learning disability, pulmonic valve stenosis, pectus excavatum, hypertelorism, and easy bruising. (less)
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Likely pathogenic
(Dec 17, 2013)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062224.6
First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017 |
Comment:
The Glu108Lys variant in SOS1 has been reported in 6 individuals with clinical f eatures of Noonan syndrome and segregated with disease in 1 affected … (more)
The Glu108Lys variant in SOS1 has been reported in 6 individuals with clinical f eatures of Noonan syndrome and segregated with disease in 1 affected relative (T artaglia 2007, Lepri 2011, LMM unpublished data). This variant has not been iden tified in large population studies. Functional studies have shown that the Glu10 8Lys variant leads to increased activation of SOS1 protein (Gureasko 2010, Smith 2013, Saliba 2013, Findlay 2013). However, these in vitro assays may not accura tely represent biological function. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance. (less)
Number of individuals with the variant: 3
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Pathogenic
(Aug 15, 2021)
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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: SCV001821270.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: SOS1 c.322G>A (p.Glu108Lys) results in a conservative amino acid change located in the Histone H2A/H2B/H3 domain (IPR007125) of the encoded protein sequence. Three … (more)
Variant summary: SOS1 c.322G>A (p.Glu108Lys) results in a conservative amino acid change located in the Histone H2A/H2B/H3 domain (IPR007125) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251142 control chromosomes. c.322G>A has been reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2007, Lepri_2011, Kauffman_2020). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of pERK (i.e., increased RAS/MAPK output) via increased membrane association (example, Smith_2013, Gureasko_2009). Two clinical diagnostic laboratories and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 27, 2023)
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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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Invitae
Accession: SCV000659144.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 20133692, 20133694). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 20133692, 20133694). 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. ClinVar contains an entry for this variant (Variation ID: 40649). This missense change has been observed in individuals with Noonan Syndrome (PMID: 17143282, 21387466). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 108 of the SOS1 protein (p.Glu108Lys). (less)
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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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Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. | Kauffman H | Pediatric research | 2021 | PMID: 33318624 |
Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café-au-lait macules. | Castellanos E | Clinical genetics | 2020 | PMID: 31573083 |
A quantitative liposome microarray to systematically characterize protein-lipid interactions. | Saliba AE | Nature methods | 2014 | PMID: 24270602 |
NMR-based functional profiling of RASopathies and oncogenic RAS mutations. | Smith MJ | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23487764 |
Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate. | Findlay GM | Cell | 2013 | PMID: 23452850 |
SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. | Lepri F | Human mutation | 2011 | PMID: 21387466 |
Allosteric gating of Son of sevenless activity by the histone domain. | Yadav KK | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20133694 |
Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. | Gureasko J | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20133692 |
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. | Tartaglia M | Nature genetics | 2007 | PMID: 17143282 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/31e0095f-919b-4660-81cd-4f5bf83b5bcb | - | - | - | - |
Text-mined citations for rs397517164 ...
HelpRecord last updated Feb 28, 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.