1-155904470-C-G

Position:

• chr1-155904470-C-G

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_006912.6(RIT1):​c.270G>C​(p.Met90Ile) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M90V) 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:10
• Conservation: PhyloP100: 6.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 265328
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr1-155904472-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 561681.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 1-155904470-C-G is Pathogenic according to our data. Variant chr1-155904470-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.270G>C	p.Met90Ile	missense_variant	5/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.321G>C	p.Met107Ile	missense_variant	5/6		NP_001243750.1
RIT1	NM_001256820.2	c.162G>C	p.Met54Ile	missense_variant	4/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.270G>C	p.Met90Ile	missense_variant	5/6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0601 - Variant affects at least one well established (essential) functional domain or motif. The Switch II domain is involved in GTP hydrolysis (PMID: 24469055), and missense variants cluster within this domain (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with Noonan syndrome, as have alternate nucleotide changes resulting in the same missense substitution (ClinVar, Mastermind). (P) 1102 - Strong phenotype match. (P) 1208 - Segregation information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25959749). 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. ClinVar contains an entry for this variant (Variation ID: 190305). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 24939608, 25959749, 27101134, 27109146). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2014	- -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	Published functional studies demonstrate increased MEK-ERK signaling compared to wild-type (Koenighofer et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24939608, 24803665, 25959749, 30732632, 34006472, 35118825, 33726816, 33686258) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 03, 2015	- -

RIT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2023

The RIT1 c.321G>C variant is predicted to result in the amino acid substitution p.Met107Ile. In the literature this variant is also referred to as c.270G>C (p.Met90Ile) via NM_006912. This variant has been reported to be de novo in individuals with Noonan syndrome (Gos et al. 2014. PubMed ID: 24939608; Koenighofer et al. 2015. PubMed ID: 25959749; Chen et al. 2019. PubMed ID: 30732632; Frisk et al. 2022. PubMed ID: 35118825). This variant was also reported to be de novo in a fetus undergoing testing for nonimmune hydrops fetalis (Al-Kouatly et al. 2021. PubMed ID: 33686258) and in another individual undergoing testing for short stature (Table S3, Fan et al. 2021. PubMed ID: 34006472). Functional studies have shown this variant alters protein function (Koenighofer et al, 2015. PubMed ID: 25959749; Yaoita et al. 2016. PubMed ID: 26714497; Castel et al. 2019. PubMed ID: 30872527). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/190305/). This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2022

The c.270G>C (p.M90I) alteration is located in exon 5 (coding exon 4) of the RIT1 gene. This alteration results from a G to C substitution at nucleotide position 270, causing the methionine (M) at amino acid position 90 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with clinical features of RASopathy; it has been reported to have occurred de novo in some individuals (Gos, 2014; Koenighofer, 2015; Yaoita, 2016; Chen, 2019). The same amino acid substitution resulting from c.270G>T has also been observed in individuals with RASopathy (Aoki, 2016; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies showed that M90I enhances RAS-MAPK signaling (Yaoita, 2016; Koenighofer, 2015; Castel, 2019). In addition, a mouse model harboring M90I had a phenotype resembling Noonan syndrome in humans (Castel, 2019). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.095	N;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D;D;D;.
REVEL	Pathogenic	0.84
Sift	Benign	0.076	T;T;T;.
Sift4G	Benign	0.094	T;T;T;.
Polyphen		1.0	D;.;.;.
Vest4		0.98
MutPred		0.62		Gain of catalytic residue at M90 (P = 0.0046);.;.;Gain of catalytic residue at M90 (P = 0.0046);
MVP		0.65
MPC		1.9
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.94

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: rs483352822; hg19: chr1-155874261; COSMIC: COSV64170843;