chr1-155904739-C-G

Variant names:

• chr1-155904739-C-G
• rs869025191
• NM_006912.6:c.229G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006912.6(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 NM_006912.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.89
• Publications: 27 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 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr1-155904738-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 228289.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.229G>C	p.Ala77Pro	missense_variant	Exon 4 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.280G>C	p.Ala94Pro	missense_variant	Exon 4 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.121G>C	p.Ala41Pro	missense_variant	Exon 3 of 5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.229G>C	p.Ala77Pro	missense_variant	Exon 4 of 6	1	NM_006912.6	ENSP00000357306.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108238

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:3

Jul 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RIT1: PM1, PM2, PM5, PP3, PS3:Supporting, PS4:Supporting -

Jan 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.
PhyloP100		5.9
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
Mutation Taster		=5/95	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: rs869025191; hg19: chr1-155874530; COSMIC: COSV64171744;