ClinVar Genomic variation as it relates to human health
NM_005633.4(SOS1):c.1656G>C (p.Arg552Ser)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005633.4(SOS1):c.1656G>C (p.Arg552Ser)
Variation ID: 12872 Accession: VCV000012872.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.1 2: 39022772 (GRCh38) [ NCBI UCSC ] 2: 39249913 (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 Apr 4, 2013 Apr 6, 2024 May 10, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005633.4:c.1656G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005624.2:p.Arg552Ser missense NM_001382394.1:c.1635G>C NP_001369323.1:p.Arg545Ser missense NM_001382395.1:c.1656G>C NP_001369324.1:p.Arg552Ser missense NC_000002.12:g.39022772C>G NC_000002.11:g.39249913C>G NG_007530.1:g.102692G>C LRG_754:g.102692G>C LRG_754t1:c.1656G>C LRG_754p1:p.Arg552Ser Q07889:p.Arg552Ser - Protein change
- R552S, R545S
- Other names
- p.R552S:AGG>AGC
- NM_005633.3(SOS1):c.1656G>C
- Canonical SPDI
- NC_000002.12:39022771:C:G
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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 |
1618 | 1721 |
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) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2018 | RCV000159177.6 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 24, 2013 | RCV000156992.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 10, 2022 | RCV000654947.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2021 | RCV000763086.4 | |
Pathogenic (2) |
reviewed by expert panel
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May 10, 2019 | RCV000787998.5 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV000856746.2 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 25, 2024 | RCV000013732.29 |
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
(May 10, 2019)
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reviewed by expert panel
Method: curation
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Noonan syndrome and Noonan-related syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000927029.1 First in ClinVar: Jul 22, 2019 Last updated: Jul 22, 2019 |
Comment:
The c.1656G>C (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a … (more)
The c.1656G>C (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). This variant has also been identified in at least 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Ser variant may impact protein function (PS3; PMID: 27304678). This residue has been identified as a hot spot. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Ser variant may impact the protein (PP3). 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_VeryStrong, PS4, PM2, PS3, PM1_Strong, PP2, PP3. (less)
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Pathogenic
(Sep 24, 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: SCV000062202.6
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
The Arg552Ser variant in SOS1 has been identified in 7 individuals with either t he clinical features of Noonan syndrome or Noonan syndrome associated with … (more)
The Arg552Ser variant in SOS1 has been identified in 7 individuals with either t he clinical features of Noonan syndrome or Noonan syndrome associated with multi ple giant-cell lesions, and occurred de novo in one of these individuals (Slezak 2010, Beneteau 2009, Tartaglia 2007, LMM unpublished data). This variant has al so not been identified in large population studies. In addition, multiple other variants affecting this position (Arg552Gly, Arg552Lys, Arg552Met, Arg552Thr) ha ve been reported in individuals with Noonan syndrome, and functional studies sho wed that another variant at the same position (Arg552Gly) caused increased and p rolonged RAS activation (Tartaglia 2007). In summary, the Arg552Ser variant meet s our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) ba sed on de novo occurrence, absence from controls, and supporting functional evid ence. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jun 10, 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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Invitae
Accession: SCV000776855.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17586837, 18651097, 18854871, 19020799, 19352411, 21387466, 22190897, 23885229, 24037001). In at least … (more)
This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17586837, 18651097, 18854871, 19020799, 19352411, 21387466, 22190897, 23885229, 24037001). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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 SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 12872). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 552 of the SOS1 protein (p.Arg552Ser). (less)
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Pathogenic
(Aug 31, 2018)
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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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Blueprint Genetics
Accession: SCV000927898.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Noonan Syndrome Panel
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
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Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999294.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Downslanted palpebral fissures (present) , Atrial septal defect (present) , Low-set, posteriorly rotated ears (present) , Umbilical hernia (present) , Pulmonic stenosis (present) , Pulmonary … (more)
Downslanted palpebral fissures (present) , Atrial septal defect (present) , Low-set, posteriorly rotated ears (present) , Umbilical hernia (present) , Pulmonic stenosis (present) , Pulmonary artery stenosis (present) , Preeclampsia (present) , Ptosis (present) , Abnormality of lateral ventricle (present) (less)
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Pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 4
Fibromatosis, gingival, 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001190418.2
First in ClinVar: Mar 31, 2019 Last updated: May 06, 2023 |
Comment:
SOS1 NM_005633.3 exon 10 p.Arg552Ser (c.1656G>C): This variant has been reported in the literature in several individuals with Noonan syndrome, including two cases reported to … (more)
SOS1 NM_005633.3 exon 10 p.Arg552Ser (c.1656G>C): This variant has been reported in the literature in several individuals with Noonan syndrome, including two cases reported to be de novo (Tartaglia 2007 PMID:17143282, Ko 2008 PMID:19020799, Beneteau 2009 PMID:19352411, Lepri 2011 PMID:21387466, Quaio 2013 PMID:24037001, Croonen 2013 PMID:23885229). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:12872). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Another variant (c.1656G>T) that gives rise to the same protein change (p.Arg552Ser) has also been reported in several individuals with Noonan syndrome (Zenker 2007 PMID:17586837, Narumi 2008 PMID:18651097, Neumann 2009 PMID:18854871). Additionally, several other variants at this amino acid position (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have also been reported in individuals with Noonan syndrome, supporting the potential functional relevance of this codon. In summary, this variant is classified as pathogenic based on the data above. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fibromatosis, gingival, 1
Noonan syndrome 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893612.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Oct 25, 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: SCV000209122.11
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
The R552S variant has been published as a de novo pathogenic variant for Noonan syndrome and as a pathogenic variant for an allelic disorder, Noonan … (more)
The R552S variant has been published as a de novo pathogenic variant for Noonan syndrome and as a pathogenic variant for an allelic disorder, Noonan like/Multiple Giant Cell Lesion syndrome (Tartaglia et al., 2007; Beneteau et al., 2009; Neumann et al., 2009). The R552S variant is not observed in large population cohorts (Lek et al., 2016). The R552S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and that is a recognized hot spot" for pathogenic variants within the SOS1 gene. Pathogenic missense variants in the same residue (R552G, R552T, R552K, R552M) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, this variant is pathogenic." (less)
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Pathogenic
(Sep 08, 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: SCV001983605.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: SOS1 c.1656G>C (p.Arg552Ser) 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.1656G>C (p.Arg552Ser) 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 250906 control chromosomes (gnomAD). p.Arg552Ser has been reported in the literature in multiple individuals affected with Noonan Syndrome, including at least two with confirmed de novo occurrence (e.g. Tartaglia_2007, Zenker_2007, Beneteau_2009, Lepri_2011, Croonen_2013). Several other missense variants at this amino acid residue (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have been reported in association with Noonan syndrome, indicating the functional importance of p.Arg552 residue, which has been defined as a hotspot for variation by the ClinGen RASopathy Variant Curation Expert Panel (PMID 29493581). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters, including the ClinGen RASopathy Variant Curation Expert Panel, (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 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: SCV002060695.1
First in ClinVar: Jan 19, 2022 Last updated: Jan 19, 2022 |
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Uncertain significance
(Mar 25, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806392.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 08, 2012)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000206715.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 1
Clinical Features:
Pulmonic stenosis (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian _ not further specified
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Pathogenic
(Nov 15, 2008)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033979.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2019 |
Comment on evidence:
In a girl with Noonan syndrome-4 (NS4; 610733) who had pigmented villonodular synovitis (PVNS), Mascheroni et al. (2008) identified a de novo heterozygous mutation in … (more)
In a girl with Noonan syndrome-4 (NS4; 610733) who had pigmented villonodular synovitis (PVNS), Mascheroni et al. (2008) identified a de novo heterozygous mutation in the SOS1 gene, resulting in an arg552-to-ser (R522S) substitution. She presented at 13 years with swelling and severe pain in her right foot and ankle. History and physical examination showed that she had multiple features of Noonan syndrome. Mascheroni et al. (2008) suggested that PVNS is a proliferative lesion that is part of the phenotypic spectrum of Noonan syndrome. Another mutation in this same codon (R552G; 182530.0004) has also been reported. (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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NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes. | Ceyhan-Birsoy O | Human mutation | 2018 | PMID: 29696744 |
Oncogenic Signaling Pathways in The Cancer Genome Atlas. | Sanchez-Vega F | Cell | 2018 | PMID: 29625050 |
Visual perception skills: a comparison between patients with Noonan syndrome and 22q11.2 deletion syndrome. | Piccini G | Genes, brain, and behavior | 2017 | PMID: 28378436 |
Inherited Disease Genetics Improves the Identification of Cancer-Associated Genes. | Zhao B | PLoS genetics | 2016 | PMID: 27304678 |
Chronic pain in Noonan Syndrome: A previously unreported but common symptom. | Vegunta S | American journal of medical genetics. Part A | 2015 | PMID: 26297936 |
External ear anomalies and hearing impairment in Noonan Syndrome. | van Trier DC | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25862627 |
Tegumentary manifestations of Noonan and Noonan-related syndromes. | Quaio CR | Clinics (Sao Paulo, Brazil) | 2013 | PMID: 24037001 |
Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients. | Croonen EA | Molecular syndromology | 2013 | PMID: 23885229 |
Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies. | Quaio CR | American journal of medical genetics. Part A | 2012 | PMID: 22488759 |
Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. | Ezquieta B | Revista espanola de cardiologia (English ed.) | 2012 | PMID: 22465605 |
RASopathies: Clinical Diagnosis in the First Year of Life. | Digilio MC | Molecular syndromology | 2011 | PMID: 22190897 |
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 |
Noonan-like/multiple giant cell lesion syndrome in two adult patients with SOS1 gene mutations. | Slezak R | Clinical dysmorphology | 2010 | PMID: 20305546 |
SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions. | Beneteau C | European journal of human genetics : EJHG | 2009 | PMID: 19352411 |
Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome. | Neumann TE | European journal of human genetics : EJHG | 2009 | PMID: 18854871 |
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 |
Pigmented villonodular synovitis in a patient with Noonan syndrome and SOS1 gene mutation. | Mascheroni E | American journal of medical genetics. Part A | 2008 | PMID: 18925667 |
Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. | Narumi Y | Journal of human genetics | 2008 | PMID: 18651097 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7b69757f-5512-4640-93f6-c926e38cf7f9 | - | - | - | - |
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Text-mined citations for rs267607079 ...
HelpRecord last updated May 08, 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.