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NM_006912.6(RIT1):c.229G>T (p.Ala77Ser) AND Noonan syndrome 8

Germline classification:
Pathogenic (3 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:
RCV001861885.6

Allele description [Variation Report for NM_006912.6(RIT1):c.229G>T (p.Ala77Ser)]

NM_006912.6(RIT1):c.229G>T (p.Ala77Ser)

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.229G>T (p.Ala77Ser)
HGVS:
  • NC_000001.11:g.155904739C>A
  • NG_033885.1:g.11664G>T
  • NM_001256820.2:c.121G>T
  • NM_001256821.2:c.280G>T
  • NM_006912.6:c.229G>TMANE SELECT
  • NP_001243749.1:p.Ala41Ser
  • NP_001243750.1:p.Ala94Ser
  • NP_008843.1:p.Ala77Ser
  • LRG_1372t1:c.229G>T
  • LRG_1372:g.11664G>T
  • LRG_1372p1:p.Ala77Ser
  • NC_000001.10:g.155874530C>A
  • NM_006912.5:c.229G>T
Protein change:
A41S
Links:
dbSNP: rs869025191
NCBI 1000 Genomes Browser:
rs869025191
Molecular consequence:
  • NM_001256820.2:c.121G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001256821.2:c.280G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006912.6:c.229G>T - 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
SCV002247029Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 17, 2021)
germlineclinical testing

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

SCV0023184533billion
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 22, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004050488Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 11, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia.

Cavé H, Caye A, Ghedira N, Capri Y, Pouvreau N, Fillot N, Trimouille A, Vignal C, Fenneteau O, Alembik Y, Alessandri JL, Blanchet P, Boute O, Bouvagnet P, David A, Dieux Coeslier A, Doray B, Dulac O, Drouin-Garraud V, Gérard M, Héron D, Isidor B, et al.

Eur J Hum Genet. 2016 Aug;24(8):1124-31. doi: 10.1038/ejhg.2015.273. Epub 2016 Jan 13.

PubMed [citation]
PMID:
26757980
PMCID:
PMC4970687

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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002247029.3

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

Description

This sequence change replaces alanine with serine at codon 77 of the RIT1 protein (p.Ala77Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala77 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26714497, 26757980, 27101134, 29402968). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 561621). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 26714497; Invitae). This variant is not present in population databases (ExAC no frequency).

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

From 3billion, SCV002318453.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with RIT1 related disorder (ClinVar ID: VCV000561621, PMID:26714497). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26714497). Different missense change at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183403, VCV000228289, VCV000850519, PMID:25049390, 26714497). It is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.809>=0.6, 3CNET: 0.994>=0.75). Missense changes are a common disease-causing mechanism. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Genome-Nilou Lab, SCV004050488.1

#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: Sep 29, 2024