rs869025191
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The ENST00000368323.8(RIT1):c.229G>T(p.Ala77Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,670 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 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
Consequence
ENST00000368323.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RIT1 | NM_006912.6 | c.229G>T | p.Ala77Ser | missense_variant | 4/6 | ENST00000368323.8 | NP_008843.1 | |
RIT1 | NM_001256821.2 | c.280G>T | p.Ala94Ser | missense_variant | 4/6 | NP_001243750.1 | ||
RIT1 | NM_001256820.2 | c.121G>T | p.Ala41Ser | 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>T | p.Ala77Ser | missense_variant | 4/6 | 1 | NM_006912.6 | ENSP00000357306 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457670Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 725490
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome 8 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 17, 2021 | This sequence change replaces alanine with serine at codon 77 of the RIT1 protein (p.Ala77Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala77 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26714497, 26757980, 27101134, 29402968). 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: 561621). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 26714497; Invitae). This variant is not present in population databases (ExAC no frequency). - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with RIT1 related disorder (ClinVar ID: VCV000561621, PMID:26714497). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26714497). Different missense change at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183403, VCV000228289, VCV000850519, PMID:25049390, 26714497). It is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.809>=0.6, 3CNET: 0.994>=0.75). Missense changes are a common disease-causing mechanism. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Noonan syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics, Centre for Human Genetics | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2019 | Published functional studies demonstrate a damaging effect; A77S confers a gain-of-function by causing significant increase in Elk1 activation in comparison to wild-type (Yaoita et al., 2016); 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: 26714497, 27109146, 29734338, 24469055) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at