NM_006912.6(RIT1):c.284G>C (p.Gly95Ala) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 29, 2019
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:: RCV001192384.1

Allele description [Variation Report for NM_006912.6(RIT1):c.284G>C (p.Gly95Ala)]

NM_006912.6(RIT1):c.284G>C (p.Gly95Ala)

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.284G>C (p.Gly95Ala)

HGVS:

NC_000001.11:g.155904456C>G
NG_033885.1:g.11947G>C
NM_001256820.2:c.176G>C
NM_001256821.2:c.335G>C
NM_006912.6:c.284G>CMANE SELECT
NP_001243749.1:p.Gly59Ala
NP_001243750.1:p.Gly112Ala
NP_008843.1:p.Gly95Ala
LRG_1372t1:c.284G>C
LRG_1372:g.11947G>C
LRG_1372p1:p.Gly95Ala
NC_000001.10:g.155874247C>G
NM_001256820.1:c.176G>C
NM_001256821.1:c.335G>C
NM_006912.4:c.284G>C
NM_006912.5:c.284G>C
Q92963:p.Gly95Ala

Protein change:

G112A; GLY95ALA

Links:

UniProtKB: Q92963#VAR_070157; OMIM: 609591.0004; dbSNP: rs672601335

NCBI 1000 Genomes Browser:

rs672601335

Molecular consequence:

NM_001256820.2:c.176G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256821.2:c.335G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006912.6:c.284G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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unnamed protein product [Homo sapiens]
unnamed protein product [Homo sapiens]
gi|7022664|dbj|BAA91679.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001360455	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 29, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23791108, 25049390, 27101134 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001360455

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 29, 2019)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Next-generation sequencing identifies rare variants associated with Noonan syndrome.

Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, Peltekova VD, Reid JG, Tworog-Dube E, Morgan MB, Muzny DM, Stein L, McPherson JD, Roberts AE, Gibbs RA, Neel BG, Kucherlapati R.

Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11473-8. doi: 10.1073/pnas.1324128111. Epub 2014 Jul 21.

PubMed [citation]

PMID:: 25049390
PMCID:: PMC4128129

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: RIT1 c.284G>C (p.Gly95Ala) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225), in the switch II region (Chen_2014) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes (gnomAD). c.284G>C has been reported in the literature in heterozygous state in several individuals affected with Noonan Syndrome and Related Conditions, including confirmed de novo occurrences, and segregation with disease in at least 1 family (Aoki_2013, Chen_2014, Kouz_2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein increases the activity of the RAS/MAPK pathway (Aoki_2013, Chen_2014). In addition, transfection of the variant into zebrafish embryos resulted in a variety of developmental defects, consistent with the disease phenotype observed in humans (Aoki_2013). Seven ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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