rs672601334

Positions:

• chr1-155904798-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_006912.6(RIT1):​c.170C>G​(p.Ala57Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 7.43

Genes affected

RIT1 (HGNC:10023): (Ras like without CAAX 1) This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

RIT1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 55 pathogenic changes around while only 10 benign (85%) in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 1-155904798-G-C is Pathogenic according to our data. Variant chr1-155904798-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 60506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904798-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.170C>G	p.Ala57Gly	missense_variant	4/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.221C>G	p.Ala74Gly	missense_variant	4/6		NP_001243750.1
RIT1	NM_001256820.2	c.62C>G	p.Ala21Gly	missense_variant	3/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.170C>G	p.Ala57Gly	missense_variant	4/6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:10

Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PS2,PM2,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 23, 2023	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Ala74Gly variant in RIT1 was identified by our study in one individual with Noonan syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in ClinVar with an alternate name, p.Ala57Gly (Variation ID: 60506). There are at least five individuals with Noonan syndrome and de novo inheritance of this variant in ClinVar and the literature (PMID: 25959749, 26714497, 23791108). In summary, the p.Ala74Gly variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 57 of the RIT1 protein (p.Ala57Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 24901346, 25049390, 25124994, 25959749, 26714497, 26757980, 27101134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60506). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) did not meet the statistical confidence thresholds required to predict the impact of this variant on RIT1 function. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25049390, 25959749, 27226556). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been reported as de novo multiple (>3) similarly affected unrelated individuals(PMID: 23791108, 25959749, 26714497, PS2_VS, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62, 3CNET: 0.822, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 8 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Aug 01, 2017	The missense variant c.221C>G, p.(Ala74Gly) in RIT1 was identified in a boy with clinically suspected Noonan syndrome and osteogenesis imperfecta due to a de novo mutation in COL1A1. The variant in RIT1 was shown to be de novo and had been reported in several other patients with Noonan syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2022	Published functional studies demonstrate that A57G enhanced ELK1 trans-activation in a luciferase assay above wild-type levels (Aoki et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25959749, 30105547, 23791108, 25049390, 25124994, 24901346, 24803665, 27226556, 30732632, 28991257, 30898653, 29158550, 31292302, 31219622, 32396283, 32368696, 34643321) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2016	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. -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

- -

RIT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2023

The RIT1 c.221C>G variant is predicted to result in the amino acid substitution p.Ala74Gly. Using an alternate transcript, this variant is also referred to as c.170C>G (p.Ala57Gly). This variant has been reported to be causative for Noonan syndrome (see for example - Aoki et al. 2013. PubMed ID: 23791108; Bertola et al. 2014. PubMed ID: 25124994; Koenighofer et al. 2016. PubMed ID: 25959749). Functional studies demonstrate this variant affects protein function (Fang et al. 2016. PubMed ID: 27226556). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2021

The p.A57G variant (also known as c.170C>G), located in coding exon 3 of the RIT1 gene, results from a C to G substitution at nucleotide position 170. The alanine at codon 57 is replaced by glycine, an amino acid with similar properties. This variant is also known as p.A74G (c.221C>G). This variant has been described in Noonan syndrome cohorts and pediatric cardiomyopathy cohorts, and it has been detected as a de novo and inherited variant in multiple unrelated individuals who meet clinical diagnostic criteria for Noonan syndrome (Aoki Y et al. Am J Hum Genet, 2013 Jul;93:173-80, Bertola DR et al. Am J Med Genet A, 2014 Nov;164A:2952-7; Chen PC et al. Proc Natl Acad Sci U S A, 2014 Aug;111:11473-8; Iglesias A et al. Genet Med, 2014 Dec;16:922-31; Cavé H et al. Eur J Hum Genet, 2016 08;24:1124-31; Kouz K et al. Genet Med, 2016 12;18:1226-1234; Yaoita M et al. Hum Genet, 2016 Feb;135:209-22; Popp B et al. Eur J Hum Genet, 2017 12;25:1364-1376; Shoji Y et al. Endocr J, 2019 Nov;66:983-994; Li X et al. Clin Genet, 2019 10;96:290-299; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29; Aly SA et al. Mol Genet Genomic Med, 2020 07;8:e1253; Rupp S et al. Clin Res Cardiol, 2019 Mar;108:282-289). Experimental studies show this variant impacts protein function and may contribute to the pathogenesis of Noonan syndrome, at least in part, through enhancing ERK1/2 pathway signaling (Aoki Y et al. Am J Hum Genet, 2013 Jul;93:173-80; Chen PC et al. Proc Natl Acad Sci U S A, 2014 Aug;111:11473-8; Fang Z et al. J Biol Chem, 2016 07;291:15641-52; Koenighofer M et al. Clin Genet, 2016 Mar;89:359-66; Meyer Zum Büschenfelde U et al. PLoS Genet, 2018 05;14:e1007370). In addition, a heterozygous A57G knock-in mouse model recapitulated the Noonan syndrome phenotypic spectrum, including the fibrotic cardiac hypertrophy that appears to be a Noonan syndrome phenotype most frequently associated with RIT1 gene mutations (Takahara S et al. EBioMedicine, 2019 Apr;42:43-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 08, 2021

Variant summary: RIT1 c.170C>G (p.Ala57Gly) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225; also called as the G2 domain, 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 252130 control chromosomes (gnomAD and publication data). c.170C>G has been reported in the literature in multiple individuals affected with Noonan Syndrome or a related phenotype, including de novo occurrences (Aoki_2013, Bertola_2014, Chen_2014, Fang_2016, Koenighofer_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant activated RAS-ERK pathway, exhibited more rapid nucleotide exchange on GTPase assay, revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism in zebrafish, exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation in mice (Chen_2014, Fang_2016, Koenighofer_2016, Takahara_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.1	N;N;N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.80
MutPred		0.74		Loss of stability (P = 0.0512);.;.;Loss of stability (P = 0.0512);
MVP		0.66
MPC		0.95
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs672601334; hg19: chr1-155874589; COSMIC: COSV64170716;