rs869025195

Variant names:

• chr1-155904493-T-G
• rs869025195
• NM_006912.6:c.247A>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_006912.6(RIT1):​c.247A>C​(p.Thr83Pro) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.52
• Publications: 13 publications found

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]

RIT1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 1-155904493-T-G is Pathogenic according to our data. Variant chr1-155904493-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 183409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.247A>C	p.Thr83Pro	missense_variant	Exon 5 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.298A>C	p.Thr100Pro	missense_variant	Exon 5 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.139A>C	p.Thr47Pro	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.247A>C	p.Thr83Pro	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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:4

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as de novo in a similarly affected individual (PMID: 23791108, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183409, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.818, 3CNET: 0.982, 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. -

May 15, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with proline at codon 83 of the RIT1 protein (p.Thr83Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. For these reasons, this variant has been classified as Pathogenic. This missense change is located in a region of the RIT1 protein where a significant number of previously reported RIT1 missense mutations are found (PMID: 26757980, 27101134). These observations suggest that this may be a clinically significant region of the protein. This variant has been reported to affect RIT1 protein function (PMID: 27226556). This variant has been observed in individual(s) with Noonan syndrome (PMID: 23791108). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183409). This variant is not present in population databases (ExAC no frequency). -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Nov 19, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 1 Pathogenic:1

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the p.(T83P) variant results in enhanced Elk1 transactivation in comparison to wild-type (PMID: 26714497); Published functional studies have also demonstrated that p.(T83P) results in an increased nucleotide exchange rate and slower GTP hydrolysis (PMID: 27226556); 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: 26757980, 34758253, 25959749, 27109146, 26446362, 27226556, 26714497, 23791108) -

Noonan syndrome Pathogenic:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Mar 16, 2020

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.247A>C (p.Thr83Pro) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes (gnomAD). c.247A>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (examples- Aoki_2013, Cave_2016, Kouz_2016). These data indicate that the variant may be associated with disease. In-vitro studies evaluating an impact on protein function showed that the variant results in impaired GTP-hydrolysis and increased activation as assessed by Ras-binding domain pull-down assays (Fang_2016) and higher levels of activation of Elk1 (Yaoita_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as 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	0.86
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	0.58	N;.;.;.
PhyloP100		6.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.0	D;D;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.68
MutPred		0.64		Loss of phosphorylation at T83 (P = 0.0846);.;.;Loss of phosphorylation at T83 (P = 0.0846);
MVP		0.86
MPC		2.1
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869025195; hg19: chr1-155874284;