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NM_006912.6(RIT1):c.170C>G (p.Ala57Gly) AND Noonan syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 10, 2016
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:
RCV000207349.7

Allele description [Variation Report for NM_006912.6(RIT1):c.170C>G (p.Ala57Gly)]

NM_006912.6(RIT1):c.170C>G (p.Ala57Gly)

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.170C>G (p.Ala57Gly)
HGVS:
  • NC_000001.11:g.155904798G>C
  • NG_033885.1:g.11605C>G
  • NM_001256820.2:c.62C>G
  • NM_001256821.2:c.221C>G
  • NM_006912.6:c.170C>GMANE SELECT
  • NP_001243749.1:p.Ala21Gly
  • NP_001243750.1:p.Ala74Gly
  • NP_008843.1:p.Ala57Gly
  • LRG_1372t1:c.170C>G
  • LRG_1372:g.11605C>G
  • LRG_1372p1:p.Ala57Gly
  • NC_000001.10:g.155874589G>C
  • NM_001256821.1:c.221C>G
  • NM_006912.4:c.170C>G
  • NM_006912.5:c.170C>G
  • Q92963:p.Ala57Gly
  • p.A57G
Protein change:
A21G; ALA57GLY
Links:
UniProtKB: Q92963#VAR_070150; OMIM: 609591.0001; dbSNP: rs672601334
NCBI 1000 Genomes Browser:
rs672601334
Molecular consequence:
  • NM_001256820.2:c.62C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256821.2:c.221C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006912.6:c.170C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
6

Condition(s)

Name:
Noonan syndrome (NS)
Synonyms:
Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:
MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000211876Service de Génétique Moléculaire, Hôpital Robert Debré

See additional submitters

no assertion criteria provided

(clinical testing)		Pathogenicpaternal, unknown, de novoclinical testing

SCV000271446Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Feb 10, 2016) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedpaternalyes1not providednot provided1not providedclinical testing
not providedde novoyes1not providednot provided1not providedclinical testing
not providedgermlinenot provided66not providednot providednot providedclinical testing
not providedunknownyes1not providednot provided1not providedclinical testing

Citations

PubMed

Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.

Kiel C, Serrano L.

Mol Syst Biol. 2014 May 6;10:727. doi: 10.1002/msb.20145092.

PubMed [citation]
PMID:
24803665
PMCID:
PMC4188041

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
See all PubMed Citations (7)

Details of each submission

From Service de Génétique Moléculaire, Hôpital Robert Debré, SCV000211876.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
2not provided1not providednot providedclinical testingnot provided
3not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyes1not providednot provided1not providednot providednot provided
2unknownyes1not providednot provided1not providednot providednot provided
3de novoyes1not providednot provided1not providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271446.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testing PubMed (7)

Description

The p.Ala74Gly variant in RIT1 (reported as p.Ala57Gly based on amino acid seque nce predicted from NM_006912.5) has been identified in more than 10 individuals with Noonan syndrome and occurred de novo in four of these individuals (Aoki 201 3, Chen 2014, Bertola 2014, Iglesias 2014, Koenighofer 2015, LMM data). It has n ot been identified in large population studies. Pathogenic variants in RIT1 clus ter in the Switch I domain of the protein, where this variant is located (Aoki 2 013, Chen 2014). In summary, this variant meets our criteria to be classified a s pathogenic for Noonan syndrome in an autosomal dominant manner based upon its de novo and over-represented occurrences in affected individuals compared to the general population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided6not provided6not provided

Last Updated: May 19, 2024