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NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
4 (Most recent: Sep 20, 2021)
Last evaluated:
Aug 5, 2021
Accession:
VCV000370035.6
Variation ID:
370035
Description:
single nucleotide variant
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NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)

Allele ID
354275
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1q22
Genomic location
1: 155904494 (GRCh38) GRCh38 UCSC
1: 155874285 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_1372:g.11909T>A
LRG_1372t1:c.246T>A LRG_1372p1:p.Phe82Leu
Q92963:p.Phe82Leu
... more HGVS
Protein change
F82L, F99L, F46L
Other names
-
Canonical SPDI
NC_000001.11:155904493:A:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA16040628
UniProtKB: Q92963#VAR_070152
dbSNP: rs730881014
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 2 criteria provided, single submitter Nov 13, 2019 RCV000408903.4
Pathogenic 1 criteria provided, single submitter Aug 5, 2021 RCV000427451.3
Pathogenic 1 criteria provided, single submitter - RCV000856765.1

Clinical features observed in individuals with this variant

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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
RIT1 - - GRCh38
GRCh37
121 135

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Noonan syndrome 1
Allele origin: unknown
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999319.1
Submitted: (Jun 02, 2019)
Evidence details
Pathogenic
(Nov 13, 2019)
criteria provided, single submitter
Method: clinical testing
Noonan syndrome 8
Allele origin: germline
Invitae
Accession: SCV000659222.3
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (8)
Comment:
This sequence change replaces phenylalanine with leucine at codon 82 of the RIT1 protein (p.Phe82Leu). The phenylalanine residue is highly conserved and there is a … (more)
Pathogenic
(Aug 05, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000534935.6
Submitted: (Sep 20, 2021)
Evidence details
Comment:
Published in vitro studies demonstrate that variant induces elevated and prolonged phosporylation of downstream targets and strongly enhances protein-proteins interactions, consistent with a gain-of-function effect … (more)
Pathogenic
(Dec 01, 2016)
no assertion criteria provided
Method: clinical testing
Noonan syndrome 8
(Autosomal dominant inheritance)
Allele origin: unknown
MVZ Praenatalmedizin und Genetik Nuernberg
Accession: SCV000484991.1
Submitted: (Dec 23, 2016)
Evidence details
Comment:
wobble base substitution results in an already described pathogenic aminoacid substitution (rs730881014; Aoki et al., 2013) and was therefore rated pathogenic here.

Functional evidence

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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 this variant

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Title Author Journal Year Link
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
The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. Joyce S European journal of human genetics : EJHG 2016 PMID: 26242988
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
Oncogenic RIT1 mutations in lung adenocarcinoma. Berger AH Oncogene 2014 PMID: 24469055
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 rs730881014...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2021