rs869025194

Variant names:

• chr1-155904496-A-C
• rs869025194
• NM_006912.6:c.244T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-155904496-A-C
• chr1-155904496-A-G
• chr1-155904496-A-T

Variant summary

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

The NM_006912.6(RIT1):​c.244T>G​(p.Phe82Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F82C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.55

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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-155904495-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 372863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 1-155904496-A-C is Pathogenic according to our data. Variant chr1-155904496-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 183408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904496-A-C is described in Lovd as [Pathogenic]. Variant chr1-155904496-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.244T>G	p.Phe82Val	missense_variant	Exon 5 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.295T>G	p.Phe99Val	missense_variant	Exon 5 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.136T>G	p.Phe46Val	missense_variant	Exon 4 of 5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.244T>G	p.Phe82Val	missense_variant	Exon 5 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:10

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183408). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23791108). Different missense changes at the same codon (p.Phe82Cys, p.Phe82Ile, p.Phe82Leu, p.Phe82Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181522 , VCV000183406 , VCV000183407 , VCV000370035 , VCV000372863 , VCV000694696). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM2, PP2, PP3, PP4, PP5 -

-

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 28, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as c.244T>G (p.F82V) on the alternate transcript NM_006912.4 (PMID: 23791108, 25049390, 24939608, 27226556). This variant has been previously reported as a de novo heterozygous change in patients with Noonan Syndrome (NS; PMID: 23791108, 25049390, 24939608, 27848944). In one study, this alteration was identified together with a variant in the RASA2 gene (p.Y326C), and both alterations increased ERK activation in in-vitro transfection experiments (PMID: 25049390). The c.295T>G (p.Phe99Val) was also identified in a 22-year-old man with recurrent infections since childhood and suspected common variable immune deficiency (PMID: 28188499). Additionally, this variant has been identified in patients with myeloid malignancies (PMID: 27226556, 23765226). Functional characterization indicates that this variant, located in the RAS switch II domain important for GTPase activity, is a gain-of-function alteration that leads to activation of the RAS-ERK pathway by impairing GTP hydrolysis (PMID: 23791108, 27226556). It is absent from the gnomAD population database and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.295T>G (p.Phe99Val) variant on protein function. Based on the available evidence, the c.295T>G (p.Phe99Val) variant is classified as Pathogenic. -

Apr 08, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Val). 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, 24939608, 25049390, 26757980, 27101134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183408). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RIT1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25049390, 26714497, 27226556). This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies demonstrate that the F82V variant results in enhanced p-ERK levels in comparison to wild-type (Chen et al., 2014; Fang et al., 2016) and increased Elk1 transactivation (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; This variant is associated with the following publications: (PMID: 26714497, 26757980, 32860008, 25049390, 23791108, 23765226, 24939608, 27226556, 27101134, 25959749, 27109146, 26446362, 34426522, 34008892) -

Noonan syndrome Pathogenic:1

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Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Jan 06, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F82V pathogenic mutation (also known as c.244T>G), located in coding exon 4 of the RIT1 gene, results from a T to G substitution at nucleotide position 244. The phenylalanine at codon 82 is replaced by valine, an amino acid with highly similar properties. This mutation was identified in multiple individuals with Noonan syndrome, including several de novo cases (Aoki Y et al. Am. J. Hum. Genet., 2013 Jul;93:173-80; Gos M et al. Am. J. Med. Genet. A, 2014 Sep;164A:2310-6; Chen PC et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Aug;111:11473-8; Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31; Fang Z et al. J. Biol. Chem., 2016 07;291:15641-52; Kouz K et al. Genet. Med., 2016 12;18:1226-1234). Functional studies demonstrated that this variant increased the GTP-loaded, activated state of RIT1 and impaired GTP hydrolysis (Fang Z et al. J. Biol. Chem., 2016 07;291:15641-52) and increased Elk1 transactivation compared to wild type (Yaoita M et al. Hum. Genet., 2016 Feb;135:209-22). In addition, a known disease-causing mutation, p.F82L, has been described in the same codon in individuals with Noonan syndrome (Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31). Based on the supporting evidence, the p.F82V alteration is interpreted as a disease-causing mutation. -

RASopathy Pathogenic:1

Oct 03, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RIT1 c.244T>G (p.Phe82Val) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005525), also referred to as the Switch II domain (Cave_2016) 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 250842 control chromosomes. c.244T>G has been reported in the literature in multiple well phenotyped and comprehensively genotyped individuals affected with Noonan Syndrome (example, Aoki_2013, Chen_2014, Gos_2014, Cave_2016, Kouz_2016, Yaoita_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in stimulation of ELK transcription (Yaoita_2016), promotes ERK activation (Chen_2014) and reduction in the rate of GTP hydrolysis (Fang_2016) consistent with a gain of function mechanism. Three 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 (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

May 10, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.1	D;D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.88
MutPred		0.88		Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);
MVP		0.85
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.97

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: rs869025194; hg19: chr1-155874287;