1-155904739-C-T

Position:

• chr1-155904739-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000368323.8(RIT1):​c.229G>A​(p.Ala77Thr) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A77G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 ENST00000368323.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.89

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 18 ACMG points.

• 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 ENST00000368323.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155904738-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 850519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 1-155904739-C-T is Pathogenic according to our data. Variant chr1-155904739-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904739-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.229G>A	p.Ala77Thr	missense_variant	4/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.280G>A	p.Ala94Thr	missense_variant	4/6		NP_001243750.1
RIT1	NM_001256820.2	c.121G>A	p.Ala41Thr	missense_variant	3/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.229G>A	p.Ala77Thr	missense_variant	4/6	1	NM_006912.6	ENSP00000357306	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 11, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 77 of the RIT1 protein (p.Ala77Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26714497, 26757980, 27101134, 29402968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183403). 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. Experimental studies have shown that this missense change affects RIT1 function (PMID: 26714497). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 27, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 07, 2024	PP3, PM2, PM6_strong, PS3_supporting, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2022	Published functional studies demonstrate that A77T acts as a gain-of-function variant, causing increased Elk1 activation and enhanced cJun transcription (Yaoita et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 183403; ClinVar); This variant is associated with the following publications: (PMID: 27109146, 27101134, 26714497, 26757980, 30692697, 29402968, 33726816) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RIT1: PS2, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Noonan syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics, Centre for Human Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -

RIT1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2024

The RIT1 c.280G>A variant is predicted to result in the amino acid substitution p.Ala94Thr. This variant has also been referred to as p.Ala77Thr in literature. This variant has been reported in multiple individuals with Noonan syndrome; three times as a de novo event and once transmitted from an affected parent (Yaoita et al. 2016. PubMed: 26714497; Cavé et al 2016. PubMed ID: 26757980; Kouz et al 2016. PubMed ID: 27101134). Different missense variants that affect the same amino acid (p.Ala94Pro, p.Ala94Ser) have also been reported to be causative for Noonan spectrum disorders (Chen et al. 2014. PubMed ID: 25049390; Yaoita. 2016. PubMed ID: 26714497). In addition, it has been identified in multiple individuals tested for Noonan spectrum disorders in our internal database. This variant is interpreted as pathogenic. This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Noonan syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 16, 2023

Variant summary: RIT1 c.229G>A (p.Ala77Thr) 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 251384 control chromosomes. c.229G>A has been reported in the literature as a de-novo occurrence in multiple individuals affected with Noonan Syndrome (example, PMID: 26757980, 26714497). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 26714497). The most pronounced variant effect results in significantly enhanced ELK transactivation, confirming the gain-of function mechanism of disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.0	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.016	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.88
MutPred		0.86		Gain of glycosylation at T76 (P = 0.1101);.;.;Gain of glycosylation at T76 (P = 0.1101);
MVP		0.84
MPC		1.6
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.79
gMVP		0.90

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: rs869025191; hg19: chr1-155874530; COSMIC: COSV64170884;