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NM_006912.6(RIT1):c.244T>G (p.Phe82Val) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 6, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002453562.2

Allele description [Variation Report for NM_006912.6(RIT1):c.244T>G (p.Phe82Val)]

NM_006912.6(RIT1):c.244T>G (p.Phe82Val)

Gene:
RIT1:Ras like without CAAX 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_006912.6(RIT1):c.244T>G (p.Phe82Val)
HGVS:
  • NC_000001.11:g.155904496A>C
  • NG_033885.1:g.11907T>G
  • NM_001256820.2:c.136T>G
  • NM_001256821.2:c.295T>G
  • NM_006912.6:c.244T>GMANE SELECT
  • NP_001243749.1:p.Phe46Val
  • NP_001243750.1:p.Phe99Val
  • NP_008843.1:p.Phe82Val
  • LRG_1372t1:c.244T>G
  • LRG_1372:g.11907T>G
  • LRG_1372p1:p.Phe82Val
  • NC_000001.10:g.155874287A>C
  • NM_001256821.1:c.295T>G
  • NM_006912.4:c.244T>G
  • NM_006912.5:c.244T>G
  • Q92963:p.Phe82Val
Protein change:
F46V; PHE82VAL
Links:
UniProtKB: Q92963#VAR_070153; OMIM: 609591.0005; dbSNP: rs869025194
NCBI 1000 Genomes Browser:
rs869025194
Molecular consequence:
  • NM_001256820.2:c.136T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256821.2:c.295T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006912.6:c.244T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002736810Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Jan 6, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, et al.

Am J Hum Genet. 2013 Jul 11;93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. Epub 2013 Jun 20.

PubMed [citation]
PMID:
23791108
PMCID:
PMC3710767

Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity.

Gos M, Fahiminiya S, PoznaƄski J, Klapecki J, Obersztyn E, Piotrowicz M, Wierzba J, Posmyk R, Bal J, Majewski J.

Am J Med Genet A. 2014 Sep;164A(9):2310-6. doi: 10.1002/ajmg.a.36646. Epub 2014 Jun 17. No abstract available.

PubMed [citation]
PMID:
24939608
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002736810.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.F82V pathogenic mutation (also known as c.244T>G), located in coding exon 4 of the RIT1 gene, results from a T to G substitution at nucleotide position 244. The phenylalanine at codon 82 is replaced by valine, an amino acid with highly similar properties. This mutation was identified in multiple individuals with Noonan syndrome, including several de novo cases (Aoki Y et al. Am. J. Hum. Genet., 2013 Jul;93:173-80; Gos M et al. Am. J. Med. Genet. A, 2014 Sep;164A:2310-6; Chen PC et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Aug;111:11473-8; Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31; Fang Z et al. J. Biol. Chem., 2016 07;291:15641-52; Kouz K et al. Genet. Med., 2016 12;18:1226-1234). Functional studies demonstrated that this variant increased the GTP-loaded, activated state of RIT1 and impaired GTP hydrolysis (Fang Z et al. J. Biol. Chem., 2016 07;291:15641-52) and increased Elk1 transactivation compared to wild type (Yaoita M et al. Hum. Genet., 2016 Feb;135:209-22). In addition, a known disease-causing mutation, p.F82L, has been described in the same codon in individuals with Noonan syndrome (Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31). Based on the supporting evidence, the p.F82V alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024