NM_006912.6(RIT1):c.247A>C (p.Thr83Pro) AND Noonan syndrome 8

Clinical significance:Pathogenic (Last evaluated: May 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001384933.2

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:
Noonan syndrome 8 (NS8)
Identifiers:
MONDO: MONDO:0014143; MedGen: C3809233; Orphanet: 648; OMIM: 615355

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001584627Invitaecriteria provided, single submitter
Pathogenic
(May 15, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001759991Genomics England Pilot Project,Genomics Englandno assertion criteria provided
Likely pathogenicgermlineclinical testing

Citation Link

Summary from all submissions

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

Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1).

Fang Z, Marshall CB, Yin JC, Mazhab-Jafari MT, Gasmi-Seabrook GM, Smith MJ, Nishikawa T, Xu Y, Neel BG, Ikura M.

J Biol Chem. 2016 Jul 22;291(30):15641-52. doi: 10.1074/jbc.M116.714196. Epub 2016 May 18.

PubMed [citation]
PMID:
27226556
PMCID:
PMC4957048
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001584627.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces threonine with proline at codon 83 of the RIT1 protein (p.Thr83Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Noonan syndrome (PMID: 23791108). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183409). This variant has been reported to affect RIT1 protein function (PMID: 27226556). This missense change is located in a region of the RIT1 protein where a significant number of previously reported RIT1 missense mutations are found (PMID: 26757980, 27101134). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.

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

From Genomics England Pilot Project,Genomics England, SCV001759991.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 6, 2021

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