Submissions for variant NM_001022.4(RPS19):c.68A>G (p.Lys23Arg)

gnomAD frequency: 0.00029  dbSNP: rs143477104

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094592	SCV000413384	benign	Diamond-Blackfan anemia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000358661	SCV000553775	uncertain significance	Diamond-Blackfan anemia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 23 of the RPS19 protein (p.Lys23Arg). This variant is present in population databases (rs143477104, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RPS19-related conditions. ClinVar contains an entry for this variant (Variation ID: 329392). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001564337	SCV001787490	uncertain significance	not provided	2019-10-28	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified as a common polymorphism in the RPS19 gene, and authors presumed this variant to be benign (Aspesi et al., 2018); This variant is associated with the following publications: (PMID: 29766597)
Genetic Services Laboratory, University of Chicago	RCV001820988	SCV002065627	uncertain significance	not specified	2020-01-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RPS19 gene demonstrated a sequence change, c.68A>G, in exon 2 that results in an amino acid change, p.Lys23Arg. This sequence change does not appear to have been previously described in patients with RPS19-related disorders and has been described in the gnomAD database with a frequency of 0.04% in European populations (dbSNP rs143477104). The p.Lys23Arg change affects a moderately conserved amino acid residue located in a domain of the RPS19 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys23Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys23Arg change remains unknown at this time.
Ambry Genetics	RCV000358661	SCV002662962	likely benign	Diamond-Blackfan anemia	2022-05-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.