1-155904496-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_006912.6(RIT1):c.244T>C(p.Phe82Leu) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.55

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 26 ACMG points.

PS1

Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 370035

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, 0.96

PP5

Variant 1-155904496-A-G is Pathogenic according to our data. Variant chr1-155904496-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 183407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904496-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6 link	c.244T>C	p.Phe82Leu	missense_variant	Exon 5 of 6	ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 link	c.295T>C	p.Phe99Leu	missense_variant	Exon 5 of 6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 link	c.136T>C	p.Phe46Leu	missense_variant	Exon 4 of 5		NP_001243749.1	Q92963-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 link	c.244T>C	p.Phe82Leu	missense_variant	Exon 5 of 6	1	NM_006912.6	ENSP00000357306.3		Q92963-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 8

Pathogenic:6

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 referred to as c.244T>C (p.Phe82Leu) in the literature due to use of an alternate transcript. The c.295T>C (p.Phe99Leu) variant has been previously reported as a de novo change in an individual with Noonan syndrome (PMID: 27699752). The p.Phe99 amino acid residue is a mutational hotspot for pathogenic variants associated with Rasopathy phenotypes (PMID: 33190430, 23791108, 30266093, 26242988, 32596782). The c.295T>C (p.Phe99Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It is absent from the gnomAD population database and thus presumed to be rare. Based on the available evidence, c.295T>C (p.Phe99Leu) is classified as Pathogenic. -

Aug 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 24939608, 25049390, 26757980, 27101134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 183407). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 27699752). In at least one individual the variant was observed to be de novo. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Leu). -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2024

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 25124994, 35627109, 35574990, 27699752, 27101134, 26757980) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RIT1-related disorder

Pathogenic:1

Dec 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RIT1 c.295T>C variant is predicted to result in the amino acid substitution p.Phe99Leu. This variant, also referred to as p.Phe82Leu (NM_006912.5), has been reported in multiple individuals with Noonan syndrome and confirmed as de novo in multiple cases (Dufke et al. 2022. PubMed ID: 35574990; Kucińska-Chahwan et al. 2022. PubMed ID: 35627109). Additionally, alternate nucleotide substitutions (c.246T>A, c.246T>G) resulting in the same missense variant have been reported as pathogenic (Aoki et al. 2013. PubMed ID: 23791108; Normand et al. 2018. PubMed ID: 30266093; Liu et al. 2020. PubMed ID: 33190430). 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

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Pathogenic:1

Jun 12, 2023

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>C (p.Phe82Leu) 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.244T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome, including several cases where it has been reported as a de novo occurrence (e.g.Cave_2016, Arroyo-Carrera_2016, Kouz_2016). These data indicate that the variant is very likely to be associated with disease. Furthermore, another variant resulting in the same amino acid change (c.246T>G, p.Phe82Leu) has been previously classified as pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 27699752, 25124994, 26757980, 27101134). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

May 01, 2020

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

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.2

M;.;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.4

D;D;D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.026

D;T;T;.

Sift4G

Benign

0.069

T;T;T;.

Polyphen

1.0

D;.;.;.

Vest4

0.97

MutPred

0.87

Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);

MVP

0.86

MPC

2.0

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over