chr19-41869043-G-A
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001022.4(RPS19):c.185G>A(p.Arg62Gln) 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62W) has been classified as Pathogenic.
Frequency
Consequence
NM_001022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPS19 | NM_001022.4 | c.185G>A | p.Arg62Gln | missense_variant | 4/6 | ENST00000598742.6 | |
RPS19 | NM_001321483.2 | c.185G>A | p.Arg62Gln | missense_variant | 4/6 | ||
RPS19 | NM_001321484.2 | c.185G>A | p.Arg62Gln | missense_variant | 4/6 | ||
RPS19 | NM_001321485.2 | c.198G>A | p.Ala66= | synonymous_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS19 | ENST00000598742.6 | c.185G>A | p.Arg62Gln | missense_variant | 4/6 | 1 | NM_001022.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Diamond-Blackfan anemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 62 of the RPS19 protein (p.Arg62Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Diamond-Blackfan anaemia (DBA) (PMID: 10753603, 12750732, 15384984, 18412286, 20378560). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 463372). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects RPS19 function (PMID: 16159874, 17053056, 17082006, 17517689, 17726054, 24952648). This variant disrupts the p.Arg62 amino acid residue in RPS19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15384984, 17517689, 18412286, 20606162). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2023 | The p.R62Q pathogenic mutation (also known as c.185G>A), located in coding exon 3 of the RPS19 gene, results from a G to A substitution at nucleotide position 185. The arginine at codon 62 is replaced by glutamine, an amino acid with highly similar properties. This mutation was first described in a 2-month-old infant with Diamond-Blackfan anemia (DBA) (Cmejla R, et al. Blood Cells Mol. Dis. 2000 Apr; 26(2):124-32). Subsequent studies have identified this mutation in additional infants and probands with DBA, and segregation with disease in families has been reported (Proust A et al. Hematol J. 2003; 4(2):132-6; Konno Y et al. Haematologica. 2010 Aug; 95(8):1293-9; Ichimura T et al. Int J Hematol. 2017 Apr;105(4):515-520; Muramatsu H. Genet. Med. 2017 07;19(7):796-802; Cole S et al. Front Genet, 2022 Jul;13:914141). This mutation has been reported to disrupt protein stability and prevent protein assembly into a mature ribosome in functional assays (Angelini M, et al. Hum. Mol. Genet. 2007 Jul; 16(14):1720-7). 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, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
RPS19-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 17, 2023 | The RPS19 c.185G>A variant is predicted to result in the amino acid substitution p.Arg62Gln. This variant has been reported in the heterozygous state in multiple unrelated individuals and families with Diamond-Blackfan anemia (DBA) (see for example, Cmejla R et al. 2000. PubMed ID: 10753603; Gazda HT et al. 2004. PubMed ID: 15384984; Konno Y et al. 2010. PubMed ID: 20378560; Ichimura T et al. 2016. PubMed ID: 27882484). In one large family, this variant segregated with DBA in 9 of 10 carriers (Cole S et al. 2022. PubMed ID: 35923690). In vitro functional studies show this variant significantly inhibits the rate of protein synthesis compared to control, is degraded more rapidly compared to control, and results in altered pre-rRNA processing leading to impaired ribosome biogenesis (Cmejlova J et al 2006. PubMed ID: 17082006; Angelini M et al 2007. PubMed ID: 17517689; Choesmel V et al. 2007 PubMed ID: 17053056). Another missense change impacting the same amino acid (p.Arg62Trp) has been reported in individuals with DBA and has also been shown to negatively impact RPS19 protein function, suggesting that the Arg62 residue is critical to protein function (Gazda HT et al 2004. PubMed ID: 15384984; Devlin et al. 2010. PubMed ID: 20606162). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, the c.185G>A (p.Arg62Gln) variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at