1-155904470-C-T
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_StrongPM1PM2PM5PP3PP5_Very_Strong
The NM_006912.6(RIT1):c.270G>A(p.Met90Ile) 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 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. M90V) has been classified as Pathogenic.
Frequency
Consequence
NM_006912.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RIT1 | NM_006912.6 | c.270G>A | p.Met90Ile | missense_variant | 5/6 | ENST00000368323.8 | NP_008843.1 | |
RIT1 | NM_001256821.2 | c.321G>A | p.Met107Ile | missense_variant | 5/6 | NP_001243750.1 | ||
RIT1 | NM_001256820.2 | c.162G>A | p.Met54Ile | missense_variant | 4/5 | NP_001243749.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome 8 Pathogenic:4Other:1
not provided, no classification provided | literature only | Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 8 (MIM#615355). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two different variants in the same codon resulting in changes to leucine and valine have also been reported as likely pathogenic and pathogenic in ClinVar respectively. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with Noonan syndrome (ClinVar. PMID: 24896146). Two alternative nucleotide changes (c.270G>T and c.270G>C) resulting in the same amino acid change as this variant (p.Met90Ile) have also been reported as pathogenic in ClinVar. (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 12, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cardio-facio-cutaneous syndrome (PMID: 23791108, 24896146, 24939608, 25959749). ClinVar contains an entry for this variant (Variation ID: 120250). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PS3, PM1, PM2, PP2, PP3, PP4, PP5 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2023 | Published functional studies have shown that the variant induces the phosphorylation of ERK through activation of MEK (Berger et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the critical Switch II domain which is involved in GTP hydrolysis (Berger et al., 2014); This variant is associated with the following publications: (PMID: 34906519, 24469055, 22980975, 23791108, 24896146, 26757980, 26714497, 33144663, 34008892, 34704406) - |
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 11, 2016 | proposed classification - variant undergoing re-assessment, contact laboratory - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2022 | Variant summary: RIT1 c.270G>A (p.Met90Ile) results in a conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.270G>A has been reported in the literature in individuals affected with Noonan Syndrome as a de novo variant (examples: Lallar_2020, Aoi_2021). The variant was reported to lead to increased RIT1 expression levels and accelerated the rate of mitotic progression in asynchronously growing cells (Cuevas-Navarro_2021). Additionally, a different variant affecting the same codon has been reported as pathogenic by our lab (p.Met90Val). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at