NM_006912.6(RIT1):c.246T>A (p.Phe82Leu) AND Noonan syndrome 8

Clinical significance:Pathogenic (Last evaluated: Nov 13, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000408903.4

Allele description [Variation Report for NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)]

NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)

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.246T>A (p.Phe82Leu)
HGVS:
  • NC_000001.11:g.155904494A>T
  • NG_033885.1:g.11909T>A
  • NM_001256820.2:c.138T>A
  • NM_001256821.2:c.297T>A
  • NM_006912.6:c.246T>AMANE SELECT
  • NP_001243749.1:p.Phe46Leu
  • NP_001243750.1:p.Phe99Leu
  • NP_008843.1:p.Phe82Leu
  • LRG_1372t1:c.246T>A
  • LRG_1372:g.11909T>A
  • LRG_1372p1:p.Phe82Leu
  • NC_000001.10:g.155874285A>T
  • NM_006912.5:c.246T>A
  • Q92963:p.Phe82Leu
Protein change:
F46L
Links:
UniProtKB: Q92963#VAR_070152; dbSNP: rs730881014
NCBI 1000 Genomes Browser:
rs730881014
Molecular consequence:
  • NM_001256820.2:c.138T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256821.2:c.297T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006912.6:c.246T>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000484991MVZ Praenatalmedizin und Genetik Nuernbergno assertion criteria providedPathogenic
(Dec 1, 2016)
unknownclinical testing

SCV000659222Invitaecriteria provided, single submitter
Pathogenic
(Nov 13, 2019)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Further evidence of the importance of RIT1 in Noonan syndrome.

Bertola DR, Yamamoto GL, Almeida TF, Buscarilli M, Jorge AA, Malaquias AC, Kim CA, Takahashi VN, Passos-Bueno MR, Pereira AC.

Am J Med Genet A. 2014 Nov;164A(11):2952-7. doi: 10.1002/ajmg.a.36722. Epub 2014 Aug 13.

PubMed [citation]
PMID:
25124994

The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome.

Joyce S, Gordon K, Brice G, Ostergaard P, Nagaraja R, Short J, Moore S, Mortimer P, Mansour S.

Eur J Hum Genet. 2016 May;24(5):690-6. doi: 10.1038/ejhg.2015.175. Epub 2015 Aug 5.

PubMed [citation]
PMID:
26242988
PMCID:
PMC4930084
See all PubMed Citations (9)

Details of each submission

From MVZ Praenatalmedizin und Genetik Nuernberg, SCV000484991.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testingnot provided

Description

wobble base substitution results in an already described pathogenic aminoacid substitution (rs730881014; Aoki et al., 2013) and was therefore rated pathogenic here.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV000659222.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces phenylalanine with leucine at codon 82 of the RIT1 protein (p.Phe82Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 26757980). ClinVar contains an entry for this variant (Variation ID: 370035). A different variant (c.246T>G) giving rise to the same protein effect observed here (p.Phe82Leu) has been reported in many individuals affected with Noonan syndrome (PMID: 23791108, 25124994, 26242988, 26714497, 26757980, 27101134), including several de novo cases. Experimental studies for this variant have also shown that it results in increased RIT1 activity in vitro (PMID: 23791108, 24469055). In addition, a different missense substitution at this codon (p.Phe82Val) has been determined to be pathogenic (PMID: 23791108, 26757980, 25049390), suggesting that the phenylalanine residue is critical for RIT1 protein function. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

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