ClinVar Genomic variation as it relates to human health
NM_006912.6(RIT1):c.104G>C (p.Ser35Thr)
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_006912.6(RIT1):c.104G>C (p.Ser35Thr)
Variation ID: 183401 Accession: VCV000183401.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155910658 (GRCh38) [ NCBI UCSC ] 1: 155880449 (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 11, 2016 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006912.6:c.104G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008843.1:p.Ser35Thr missense NM_001256820.2:c.-2-152G>C intron variant NM_001256821.2:c.155G>C NP_001243750.1:p.Ser52Thr missense NC_000001.11:g.155910658C>G NC_000001.10:g.155880449C>G NG_033885.1:g.5745G>C LRG_1372:g.5745G>C LRG_1372t1:c.104G>C LRG_1372p1:p.Ser35Thr Q92963:p.Ser35Thr - Protein change
- S35T, S52T
- Other names
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- Canonical SPDI
- NC_000001.11:155910657: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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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RIT1 | - | - |
GRCh38 GRCh37 |
299 | 322 |
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
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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, single submitter
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Feb 11, 2016 | RCV000207341.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 16, 2022 | RCV000255076.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000475746.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 8, 2023 | RCV003235080.1 |
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
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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
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
(Jul 12, 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: SCV000927787.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 |
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Pathogenic
(Feb 11, 2016)
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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: SCV000271444.3
First in ClinVar: May 29, 2016 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Pathogenic
(Jun 16, 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: SCV000322155.10
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate S35T results in enhanced ELK1 transactivation and altered GDP/GTP binding activities (Aoki et al., 2013; Fang et al. 2016); Not observed … (more)
Published functional studies demonstrate S35T results in enhanced ELK1 transactivation and altered GDP/GTP binding activities (Aoki et al., 2013; Fang et al. 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25049390, 27226556, 25124994, 25959749, 26757980, 26714497, 28666118, 27101134, 30898653, 29595814, 23791108) (less)
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Pathogenic
(May 08, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933860.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: RIT1 c.104G>C (p.Ser35Thr) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. … (more)
Variant summary: RIT1 c.104G>C (p.Ser35Thr) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251328 control chromosomes (gnomAD). c.104G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Aoki_2013, Bertola_2014, Kouz), including some cases where the variant was confirmed to have arisen de novo (Kouz_2016). 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, demonstrating the variant causes gain-of-function, which is a known mechanism of disease (e.g. Fang_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23791108, 25124994, 27226556, 27101134). Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 8
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004050504.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 8
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000541752.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 35 of the RIT1 protein (p.Ser35Thr). … (more)
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 35 of the RIT1 protein (p.Ser35Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 23791108, 25124994, 26714497, 26757980, 27101134). ClinVar contains an entry for this variant (Variation ID: 183401). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 27226556). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 8
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893223.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
(clinical testing)
Method: clinical testing
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Noonan's syndrome
Affected status: yes
Allele origin:
unknown
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Service de Génétique Moléculaire, Hôpital Robert Debré
Additional submitter:
Service de Génétique Clinique, Hôpital Robert Debré
Accession: SCV000211874.1
First in ClinVar: Feb 11, 2016 Last updated: Feb 11, 2016 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
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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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Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1). | Fang Z | The Journal of biological chemistry | 2016 | PMID: 27226556 |
Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. | Kouz K | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 27101134 |
Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. | Cavé H | European journal of human genetics : EJHG | 2016 | PMID: 26757980 |
Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. | Yaoita M | Human genetics | 2016 | PMID: 26714497 |
Further evidence of the importance of RIT1 in Noonan syndrome. | Bertola DR | American journal of medical genetics. Part A | 2014 | PMID: 25124994 |
Next-generation sequencing identifies rare variants associated with Noonan syndrome. | Chen PC | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 25049390 |
Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. | Aoki Y | American journal of human genetics | 2013 | PMID: 23791108 |
Text-mined citations for rs869025189 ...
HelpRecord last updated Mar 05, 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.