rs672601335

Positions:

• chr1-155904456-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_006912.6(RIT1):​c.284G>C​(p.Gly95Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• 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 16 ACMG points.

• PM1: In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 1-155904456-C-G is Pathogenic according to our data. Variant chr1-155904456-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 60509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904456-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.284G>C	p.Gly95Ala	missense_variant	5/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.335G>C	p.Gly112Ala	missense_variant	5/6		NP_001243750.1
RIT1	NM_001256820.2	c.176G>C	p.Gly59Ala	missense_variant	4/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.284G>C	p.Gly95Ala	missense_variant	5/6	1	NM_006912.6	ENSP00000357306	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 16, 2022	RIT1 NM_006912.5 exon 5 p.Gly95Ala (c.284G>C): This variant has been reported in the literature in at least 11 individuals with Noonan syndrome (Aoki 2013 PMID:23791108, Chen 2013 PMID:25049390, Bertola 2014 PMID:25124994, Gos 2014 PMID:24939608, Milosavljević 2016 PMID:27109146); two of these individuals were identified as de novo (Aoki 2013 PMID:23791108). This variant was also reported in at least 2 additional individuals with features of a RAS-opathy (Yaoita 2016 PMID:26714497) as de novo. This variant is not present in large control databases but is present in ClinVar with several labs classifying this variant as pathogenic (Variation ID:60509). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In-vivo functional studies in zebrafish also support a deleterious effect of this variant (Aoki 2013 PMID:23791108). In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome (MIM#615335). Disease-causing variants have been shown to result in increased phosphorylation of ERK1/2, increased transactivation of ELK1, and enhanced protein complex formation (PMID: 23791108, 29734338). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional Switch II domain. The Switch II domain is involved in protein-protein interactions, and pathogenic variants in this domain result in enhanced protein complex formation (PMID: 29734338). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as pathogenic in many individuals with Noonan syndrome (ClinVar, LOVD, PMID: 23791108, 26714497). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant results in in increased phosphorylation of ERK1/2, increased transactivation of ELK1, and enhanced protein complex formation (PMID: 23791108, 29734338). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed; LABID). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RIT1 function (PMID: 23791108, 25049390, 27226556). 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. ClinVar contains an entry for this variant (Variation ID: 60509). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 2439608, 23791108, 25049390, 25124994, 26714497, 26757980, 27101134, 27109146). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the RIT1 protein (p.Gly95Ala). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000060509). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 23791108, 26714497). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23791108, 26714497). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 19, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 05, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	Published functional studies demonstrate increased activity of the RIT1 protein compared to wild type (PMID: 23791108); Reported previously in association with Noonan spectrum disorders (PMID: 24939608); 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: 27109146, 25959749, 25124994, 25049390, 26757980, 26446362, 27226556, 24803665, 26714497, 23791108, 27101134, 34643321, 35904599, 24939608) -

Noonan syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	The p.Gly112Ala variant in RIT1 (also reported as p.Gly95Ala on transcript NM_00 6912.5) has been reported in at least 9 individuals with clinical features of No onan syndrome including 2 de novo occurrences (Aoki 2013, Bertola 2014, Chen 201 4, Gos 2014), and was absent from large population studies. In vitro functional studies provide conflicting evidence on the impact of the p.Gly112Ala variant on protein function (Aoki 2013, Chen 2014), but these types of assays may not accu rately represent biological function. However, animal models in the zebrafish ha ve shown that this variant causes developmental anomalies similar to those seen in Noonan syndrome (Aoki 2013). In summary, this variant meets our criteria to b e classified as pathogenic for Noonan syndrome in an autosomal dominant manner ( http://www.partners.org/personalizedmedicine/LMM) based upon de novo occurrences , absence from controls, and functional evidence. -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

RIT1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The RIT1 c.335G>C variant is predicted to result in the amino acid substitution p.Gly112Ala. This variant is also referred to as p.Gly95Ala in an alternate transcript (NM_006912.6). This variant has been reported in at least 11 individuals with Noonan syndrome and was documented as a de novo event in at least two individuals (Aoki et al. 2013. PubMed ID: 23791108; Bertola et al. 2014. PubMed ID: 25124994; Chen et al. 2014. PubMed ID: 25049390; Gos et al. 2014. PubMed ID: 24939608; Milosavljević et al. 2016. PubMed ID: 27109146). Functional studies provide conflicting evidence on the effect of this variant on RIT1 function (Aoki et al. 2013. PubMed ID: 23791108; Chen et al. 2014. PubMed ID: 25049390). In ClinVar, this variant has been interpreted as pathogenic by multiple clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/60509/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2019

The p.G95A pathogenic mutation (also known as c.284G>C), located in coding exon 4 of the RIT1 gene, results from a G to C substitution at nucleotide position 284. The glycine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration has been observed in multiple individuals with Noonan syndrome (Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31; Milosavljevi D et al. Am. J. Med. Genet. A, 2016 07;170:1874-80; Chen PC et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Aug;111:11473-8; Bertola DR et al. Am. J. Med. Genet. A, 2014 Nov;164A:2952-7; Kouz K et al. Genet. Med., 2016 12;18:1226-1234; Gos M et al. Am. J. Med. Genet. A, 2014 Sep;164A:2310-6) and occurred de novo in three individuals with Noonan syndrome (Aoki Y et al. Am. J. Hum. Genet., 2013 Jul;93:173-80; Yaoita M et al. Hum. Genet., 2016 Feb;135:209-22). Based on the available evidence, this variant is classified as a pathogenic mutation. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 29, 2019

Variant summary: RIT1 c.284G>C (p.Gly95Ala) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225), in the switch II region (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 251438 control chromosomes (gnomAD). c.284G>C has been reported in the literature in heterozygous state in several individuals affected with Noonan Syndrome and Related Conditions, including confirmed de novo occurrences, and segregation with disease in at least 1 family (Aoki_2013, Chen_2014, Kouz_2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein increases the activity of the RAS/MAPK pathway (Aoki_2013, Chen_2014). In addition, transfection of the variant into zebrafish embryos resulted in a variety of developmental defects, consistent with the disease phenotype observed in humans (Aoki_2013). Seven ClinVar submissions (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

Aug 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D;D;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.011	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.94		Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);
MVP		0.88
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs672601335; hg19: chr1-155874247;