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NM_006912.6(RIT1):c.270G>C (p.Met90Ile) AND Noonan syndrome 8

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Apr 11, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000170493.18

Allele description [Variation Report for NM_006912.6(RIT1):c.270G>C (p.Met90Ile)]

NM_006912.6(RIT1):c.270G>C (p.Met90Ile)

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.270G>C (p.Met90Ile)
HGVS:
  • NC_000001.11:g.155904470C>G
  • NG_033885.1:g.11933G>C
  • NM_001256820.2:c.162G>C
  • NM_001256821.2:c.321G>C
  • NM_006912.6:c.270G>CMANE SELECT
  • NP_001243749.1:p.Met54Ile
  • NP_001243750.1:p.Met107Ile
  • NP_008843.1:p.Met90Ile
  • LRG_1372t1:c.270G>C
  • LRG_1372:g.11933G>C
  • LRG_1372p1:p.Met90Ile
  • NC_000001.10:g.155874261C>G
  • NM_001256821.1:c.321G>C
  • NM_006912.4:c.270G>C
  • NM_006912.5:c.270G>C
  • Q92963:p.Met90Ile
Protein change:
M107I; MET90ILE
Links:
UniProtKB: Q92963#VAR_070156; OMIM: 609591.0006; dbSNP: rs483352822
NCBI 1000 Genomes Browser:
rs483352822
Molecular consequence:
  • NM_001256820.2:c.162G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256821.2:c.321G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006912.6:c.270G>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
SCV000222925OMIM
no assertion criteria provided
Pathogenic
(Sep 1, 2014)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000659223Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Oct 22, 2022)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000680026Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 25, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001482334Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
no assertion criteria provided
Pathogenic
(May 31, 2019)
de novoresearch

SCV004050466Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Apr 11, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedde novoyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlinenonot 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, Poznański 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 (8)

Details of each submission

From OMIM, SCV000222925.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a 5.5-year-old Polish girl with Noonan syndrome-8 (NS8; 615355), Gos et al. (2014) identified a de novo heterozygous c.270G-C transversion (c.270G-C, NM_006912) in the RIT1 gene, resulting in a met90-to-ile (M90I) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed.

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

From Invitae, SCV000659223.5

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25959749). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt RIT1 function. ClinVar contains an entry for this variant (Variation ID: 190305). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 24939608, 25959749, 27101134, 27109146). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile).

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV000680026.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0601 - Variant affects at least one well established (essential) functional domain or motif. The Switch II domain is involved in GTP hydrolysis (PMID: 24469055), and missense variants cluster within this domain (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with Noonan syndrome, as have alternate nucleotide changes resulting in the same missense substitution (ClinVar, Mastermind). (P) 1102 - Strong phenotype match. (P) 1208 - Segregation information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign

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

From Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital, SCV001482334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV004050466.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024