NM_006912.6(RIT1):c.247A>C (p.Thr83Pro) AND Rasopathy

Clinical significance:Pathogenic (Last evaluated: Mar 16, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001175490.1

Allele description [Variation Report for NM_006912.6(RIT1):c.247A>C (p.Thr83Pro)]

NM_006912.6(RIT1):c.247A>C (p.Thr83Pro)

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.247A>C (p.Thr83Pro)
HGVS:
  • NC_000001.11:g.155904493T>G
  • NG_033885.1:g.11910A>C
  • NM_001256820.2:c.139A>C
  • NM_001256821.2:c.298A>C
  • NM_006912.6:c.247A>CMANE SELECT
  • NP_001243749.1:p.Thr47Pro
  • NP_001243750.1:p.Thr100Pro
  • NP_008843.1:p.Thr83Pro
  • LRG_1372t1:c.247A>C
  • LRG_1372:g.11910A>C
  • LRG_1372p1:p.Thr83Pro
  • NC_000001.10:g.155874284T>G
  • NM_006912.4:c.247A>C
  • NM_006912.5:c.247A>C
  • Q92963:p.Thr83Pro
Protein change:
T100P
Links:
UniProtKB: Q92963#VAR_070154; dbSNP: rs869025195
NCBI 1000 Genomes Browser:
rs869025195
Molecular consequence:
  • NM_001256820.2:c.139A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256821.2:c.298A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006912.6:c.247A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Rasopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: CN166718

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001339083Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 16, 2020)
germlineclinical testing

PubMed (6)
[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

Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.

Kouz K, Lissewski C, Spranger S, Mitter D, Riess A, Lopez-Gonzalez V, Lüttgen S, Aydin H, von Deimling F, Evers C, Hahn A, Hempel M, Issa U, Kahlert AK, Lieb A, Villavicencio-Lorini P, Ballesta-Martinez MJ, Nampoothiri S, Ovens-Raeder A, Puchmajerová A, Satanovskij R, Seidel H, et al.

Genet Med. 2016 Dec;18(12):1226-1234. doi: 10.1038/gim.2016.32. Epub 2016 Apr 21.

PubMed [citation]
PMID:
27101134
See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339083.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: RIT1 c.247A>C (p.Thr83Pro) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes (gnomAD). c.247A>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (examples- Aoki_2013, Cave_2016, Kouz_2016). These data indicate that the variant may be associated with disease. In-vitro studies evaluating an impact on protein function showed that the variant results in impaired GTP-hydrolysis and increased activation as assessed by Ras-binding domain pull-down assays (Fang_2016) and higher levels of activation of Elk1 (Yaoita_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Oct 6, 2021

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