1-155904739-C-G

Position:

• chr1-155904739-C-G

Variant summary

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

The ENST00000368323.8(RIT1):​c.229G>C​(p.Ala77Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,666 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A77G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIT1 ENST00000368323.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.89

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000368323.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155904738-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 850519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 1-155904739-C-G is Pathogenic according to our data. Variant chr1-155904739-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.229G>C	p.Ala77Pro	missense_variant	4/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.280G>C	p.Ala94Pro	missense_variant	4/6		NP_001243750.1
RIT1	NM_001256820.2	c.121G>C	p.Ala41Pro	missense_variant	3/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.229G>C	p.Ala77Pro	missense_variant	4/6	1	NM_006912.6	ENSP00000357306	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457666 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725490

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 08, 2021	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the p.Ala77 amino acid residue in RIT1 have been observed in affected individuals (PMID: 26714497, 2657980, 27101134). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that cells expressing this variant demonstrate enhanced p-ERK levels compared with wildtype (PMID: 25049390). This variant has been reported in an individual with Noonan syndrome (PMID: 25049390). ClinVar contains an entry for this variant (Variation ID: 228289). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 77 of the RIT1 protein (p.Ala77Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2023

Published previously in association with Noonan syndrome (Chen et al., 2014; Cav et al., 2016); Published functional studies demonstrate a damaging effect through increased RAS-ERK pathway activation (Chen et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26757980, 27226556, 26446362, 24803665, 25959749, 27101134, 30904604, 25049390) -

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 03, 2016

The p.Ala94Pro variant in RIT1 (reported as p.Ala77Pro on NM_006912.5) has been identified in 1 individual with Noonan syndrome (Chen 2014). It was absent from large population studies. In vitro functional studies suggest that this variant promotes ERK activation (Chen 2014); however, these assays may not accurately re present biological function. In addition, another variant at the same position ( p.Ala77Thr) has been reported in 2 individuals with Noonan syndrome, occurring d e novo in one family and segregating with the disease in 1 affected family membe r in the other family (Cave 2016). Computational prediction tools and conservati on analysis suggest that the p.Ala94Pro variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical signif icance, the p.Ala94Pro variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D;D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.83		Loss of catalytic residue at A77 (P = 0.0057);.;.;Loss of catalytic residue at A77 (P = 0.0057);
MVP		0.89
MPC		2.1
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
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: rs869025191; hg19: chr1-155874530; COSMIC: COSV64171744;