ClinVar Genomic variation as it relates to human health
NM_005633.4(SOS1):c.1322G>A (p.Cys441Tyr)
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.1322G>A (p.Cys441Tyr)
Variation ID: 40673 Accession: VCV000040673.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.1 2: 39023106 (GRCh38) [ NCBI UCSC ] 2: 39250247 (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 Feb 24, 2015 Jun 17, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005633.4:c.1322G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005624.2:p.Cys441Tyr missense NM_001382394.1:c.1301G>A NP_001369323.1:p.Cys434Tyr missense NM_001382395.1:c.1322G>A NP_001369324.1:p.Cys441Tyr missense NC_000002.12:g.39023106C>T NC_000002.11:g.39250247C>T NG_007530.1:g.102358G>A LRG_754:g.102358G>A LRG_754t1:c.1322G>A LRG_754p1:p.Cys441Tyr Q07889:p.Cys441Tyr - Protein change
- C441Y, C434Y
- Other names
- p.C441Y:TGT>TAT
- Canonical SPDI
- NC_000002.12:39023105: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
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
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
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. |
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SOS1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1617 | 1718 |
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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV000159166.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2017 | RCV000154314.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000534974.12 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002467511.8 |
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
(Mar 20, 2017)
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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: SCV000203975.5
First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Cys441Tyr variant in SOS1 has been previously identified in six individual s with clinical features of Noonan syndrome, including two confirmed de novo occ … (more)
The p.Cys441Tyr variant in SOS1 has been previously identified in six individual s with clinical features of Noonan syndrome, including two confirmed de novo occ urrence (Tartaglia 2007, Zenker 2007, Lepri 2011, Korean Mutation Database, LMM data). This variant has not been identified in large population studies. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal do minant Noonan spectrum disorder based on presence in multiple affected individua ls including de novo occurrences. (less)
Number of individuals with the variant: 3
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Pathogenic
(Jun 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011146.8
First in ClinVar: Jul 16, 2023 Last updated: Jun 17, 2024 |
Comment:
SOS1: PM6:Strong, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Nov 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001477572.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The SOS1 c.1322G>A; p.Cys441Tyr variant (rs727504295) is reported in the literature in multiple individuals affected with Noonan syndrome (Bessis 2019, Ko 2008, Lepri 2011, Pierpont … (more)
The SOS1 c.1322G>A; p.Cys441Tyr variant (rs727504295) is reported in the literature in multiple individuals affected with Noonan syndrome (Bessis 2019, Ko 2008, Lepri 2011, Pierpont 2010, Tartaglia 2007, Zenker 2007). In at least one affected individual, the variant was not observed in either parent, suggesting a de novo origin (Tartaglia 2007). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at amino acid 441 is highly conserved, and while functional studies indicate wildtype activation of pERK (Smith 2013), the variant also exhibits increased PIP2-dependent nucleotide exchange rates (Gureasko 2010). Additionally, other amino acid substitutions at nearby codons (p.Glu433Lys, p.Gly434Arg, p.Ile437Thr) have been reported in individuals with Noonan syndrome and are considered disease-causing (Lepri 2011, Tartaglia 2007, Zenker 2007), suggesting this region is functionally important. Based on available information, the p.Cys441Tyr variant is considered to be pathogenic. References: Bessis et al. Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. Br J Dermatol. 2019 Jun;180(6):1438-1448. Gureasko J et al. Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3430-5. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Lepri F et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011 Jul;32(7):760-72. Pierpont EI et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010 Mar;152A(3):591-600. Smith et al. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9. Tartaglia et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan;39(1):75-9. Zenker M et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007 Oct;44(10):651-6. (less)
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Pathogenic
(Aug 06, 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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Invitae
Accession: SCV000659127.3
First in ClinVar: Dec 26, 2017 Last updated: May 10, 2021 |
Comment:
This sequence change replaces cysteine with tyrosine at codon 441 of the SOS1 protein (p.Cys441Tyr). The cysteine residue is highly conserved and there is a … (more)
This sequence change replaces cysteine with tyrosine at codon 441 of the SOS1 protein (p.Cys441Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome, including multiple de novo observations (PMID: 20186801, 21387466, 19077116, 17586837, 19020799 17143282, 17586837). ClinVar contains an entry for this variant (Variation ID: 40673). Experimental studies have shown that this missense change induces ERK activation similar to wild type, but increases SOS1 activity in a PIP2-dependent manner (PMID: 23487764, 20133692). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 4
Affected status: unknown
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002763425.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jan 17, 2023)
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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: SCV000209111.12
First in ClinVar: Feb 24, 2015 Last updated: Feb 07, 2023 |
Comment:
Observed in many individuals in published literature with an SOS1-related disorder (Zenker et al., 2007; Pierpont et al., 2010; Lepri et al., 2011; Chinton et … (more)
Observed in many individuals in published literature with an SOS1-related disorder (Zenker et al., 2007; Pierpont et al., 2010; Lepri et al., 2011; Chinton et al., 2019; Shoji et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate normal to increased SOS1 activity (Gureasko et al., 2010, Smith et al., 2013); This variant is associated with the following publications: (PMID: 17143282, 24803665, 30417923, 31292302, 31560489, 19077116, 23487764, 17586837, 20186801, 12628188, 21387466, 29493581, 20648242, 34643321, 20133692) (less)
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Pathogenic
(Jan 09, 2024)
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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: SCV004804324.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: SOS1 c.1322G>A (p.Cys441Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SOS1 c.1322G>A (p.Cys441Tyr) results in a non-conservative amino acid change in 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 251002 control chromosomes. c.1322G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome including a de novo occurrence (e.g. Pierpont_2008, Ko_2008, Tartaglia_2007, Alfieri_2008, Lepri_2011, Lee_2011.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Gureasko_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19077116, 19020799, 17143282, 19568997, 20133692, 21387466, 21784453). ClinVar contains an entry for this variant (Variation ID: 40673). Based on the evidence outlined above, the variant was classified as pathogenic. (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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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 |
Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. | Lee BH | The Journal of pediatrics | 2011 | PMID: 21784453 |
SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. | Lepri F | Human mutation | 2011 | PMID: 21387466 |
Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. | Pierpont EI | American journal of medical genetics. Part A | 2010 | PMID: 20186801 |
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 |
Genotype differences in cognitive functioning in Noonan syndrome. | Pierpont EI | Genes, brain, and behavior | 2009 | PMID: 19077116 |
Visual function in Noonan and LEOPARD syndrome. | Alfieri P | Neuropediatrics | 2008 | PMID: 19568997 |
PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. | Ko JM | Journal of human genetics | 2008 | PMID: 19020799 |
SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. | Zenker M | Journal of medical genetics | 2007 | PMID: 17586837 |
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. | Tartaglia M | Nature genetics | 2007 | PMID: 17143282 |
Text-mined citations for rs727504295 ...
HelpRecord last updated Jun 23, 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.