rs869025193

Positions:

• chr1-155904498-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_006912.6(RIT1):​c.242A>G​(p.Glu81Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E81Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 6.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155904499-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 183404.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 1-155904498-T-C is Pathogenic according to our data. Variant chr1-155904498-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904498-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.242A>G	p.Glu81Gly	missense_variant	5/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.293A>G	p.Glu98Gly	missense_variant	5/6		NP_001243750.1
RIT1	NM_001256820.2	c.134A>G	p.Glu45Gly	missense_variant	4/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.242A>G	p.Glu81Gly	missense_variant	5/6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183405, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported to be associated with RIT1 related disorder (ClinVar ID: VCV000183404, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.902, 3CNET: 0.991, 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 81 of the RIT1 protein (p.Glu81Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 23791108, 26757980). ClinVar contains an entry for this variant (Variation ID: 183405). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	May 10, 2023	Heterozygous variant NM_006912.6:c.242A>G in RIT1 gene was found on the WES data in female proband, 20 y.o., sporadic case, with Noonan syndrome and diffuse generalized cardiac hypertrophy . The c.242A>G is absent in The Genome Aggregation Database (gnomAD) (Date of access: 05-05-2023). In accordance with ACMG(2015) criteria this variant is classified as a pathogenic variant with the following criteria selected: PS4_Supporting, PS3, PM2, PM6, PP3, (PP5). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 06, 2023	PP3, PM1, PM2_supporting, PM6, PS3_moderate, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2024	Published functional studies demonstrated that zebrafish embryos injected with RIT1 mRNA carrying p.(E81G) exhibit craniofacial and heart defects (PMID: 23791108); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23765226, 26446362, 24803665, 25959749, 33794220, 33128510, 26757980, 28347726, 37264205, 23791108) -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2016	The p.Glu98Gly (also reported as p.Glu81Gly) variant in RIT1 has been identified in 4 individuals with clinical features of Noonan Syndrome, one of which was de novo, and segregated with disease in 3 affected relatives (Aoki 2013 and Cave 2 016, Cave personal communication). This variant was absent from large population studies. In vitro functional studies provide some evidence that this variant ma y impact protein function (Aoki 2013). In addition, an animal model in zebrafish has shown that this variant causes developmental defects similar to those seen in zebrafish with gain-of-function NRAS variants (Aoki 2013). Computational pred iction tools and conservation analysis suggest that the p.Glu98Gly variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the p.Glu98Gly variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 05, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2018

- -

RIT1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2024

The RIT1 c.293A>G variant is predicted to result in the amino acid substitution p.Glu98Gly. This variant is also known as c.242A>G (p.Glu81Gly) in the literature. This variant has been reported in at least four unrelated individuals with Noonan syndrome, including one de novo case (Aoki et al. 2013. PubMed ID: 23791108; Cavé et al. 2016. PubMed ID: 26757980; Ramond et al. 2017. PubMed ID: 28347726). In vitro functional studies suggested that this variant could lead to gain of function in the mutant RIT1 protein, and a zebrafish disease model showed craniofacial and cardiac defects (Aoki et al. 2013. PubMed ID: 23791108). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 08, 2023

Variant summary: RIT1 c.242A>G (p.Glu81Gly) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) 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 250506 control chromosomes (gnomAD). c.242A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions (e.g. Aoki_2013, Cave_2016, Ramond_2017, Bell_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer significantly increased transcriptional activity by ELK1 compared to the WT (Aoki_2013), consistent with the established gain-of-function mechanism of disease for RIT1. Furthermore, zebrafish embryos with the variant displayed heart and facial abnormalities, with a small percentage of them being severely disorganized (Aoki_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23791108, 33794220, 26757980, 28347726). Nine ClinVar submitters have assessed the variant since 2014: eight have classified the variant as pathogenic, and one as likely 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

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	D;D;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.68		Loss of stability (P = 0.0698);.;.;Loss of stability (P = 0.0698);
MVP		0.91
MPC		2.0
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs869025193; hg19: chr1-155874289;