1-155910695-T-G

Variant names:

• chr1-155910695-T-G
• rs869312687
• NM_006912.6:c.67A>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_006912.6(RIT1):​c.67A>C​(p.Lys23Gln) 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. K23N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 4.48

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 strand (size 5) in uniprot entity RIT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr1-155910693-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 581105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 1-155910695-T-G is Pathogenic according to our data. Variant chr1-155910695-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224122.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.67A>C	p.Lys23Gln	missense_variant	Exon 2 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.118A>C	p.Lys40Gln	missense_variant	Exon 2 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.-2-189A>C		intron_variant	Intron 1 of 4		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.67A>C	p.Lys23Gln	missense_variant	Exon 2 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:2

Jun 09, 2015

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 23 of the RIT1 protein (p.Lys23Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 28554332; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224122). 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%. This variant disrupts the p.Lys23 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26518681, 27101134, 29734338; 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. -

Hypertelorism;C0239340:Pedal edema;C0349588:Short stature;C0423110:Downslanted palpebral fissures Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 18, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26518681, 28554332) -

Cardiovascular phenotype Pathogenic:1

Aug 09, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K23Q variant (also known as c.67A>C), located in coding exon 1 of the RIT1 gene, results from an A to C substitution at nucleotide position 67. The lysine at codon 23 is replaced by glutamine, an amino acid with similar properties. This variant has been detected in individuals with features consistent with Noonan syndrome, including a de novo occurrence (Bowling KM et al. Genome Med, 2017 May;9:43; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Nov 15, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys40Gln variant in RIT1 has not been previously reported in individuals with clinical fe atures of a RASopathy and is absent from large population studies. However, anot her variant at the same position (p.Lys40Asn; reported as p.Lys23Asn on NM_00691 2.5) was identified as a de novo variant in 1 individual with Noonan syndrome (N emcikova 2015), suggesting changes at this position are not tolerated. Computati onal prediction tools and conservation analysis suggest that the p.Lys40Gln vari ant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathoge nic role, the clinical significance of the p.Lys40Gln variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.99	D;.;.
Vest4		0.81
MutPred		0.73		Loss of methylation at K23 (P = 0.0045);.;Loss of methylation at K23 (P = 0.0045);
MVP		0.94
MPC		1.9
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.98

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: rs869312687; hg19: chr1-155880486;