ClinVar Miner

Submissions for variant NM_020320.5(RARS2):c.1406G>A (p.Arg469His)

gnomAD frequency: 0.00001  dbSNP: rs759331139
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757711 SCV000886037 likely pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing The RARS2 c.1406G>A; p.Arg469His variant (rs759331139) was detected in the homozygous state in two siblings diagnosed with pontocerebellar hypoplasia type 6 (Cassandrini 2013). This variant is located within the tRNA binding site of the protein (Datt 2014) and functional studies in yeast have shown that this variant protein is incapable of supporting respiration (Cassandrini 2013). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at position 469 is highly conserved, considering 12 species. Based on the available information, the p.Arg469His variant is likely to be pathogenic.
GeneDx RCV000757711 SCV001765765 likely pathogenic not provided 2019-09-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect by complete loss of respiration in yeast harboring MSR1-R531H mutation (equivalent to human R469H) (Cassandrini et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in two siblings with pontocerebellar hypoplasia type 6 who also harbored a variant on the opposite allele (in trans) (Cassandrini et al., 2013); This variant is associated with the following publications: (PMID: 22569581, 30006346)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282353 SCV002572005 likely pathogenic Pontoneocerebellar hypoplasia 2023-12-22 criteria provided, single submitter clinical testing Variant summary: RARS2 c.1406G>A (p.Arg469His) results in a non-conservative amino acid change located in the DALR anticodon binding domain (IPR008909) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249724 control chromosomes. c.1406G>A has been reported in the literature as a compound heterozygous genotype in at-least two affected siblings from a family affected with Pontocerebellar Hypoplasia, Type 6, who continue to be cited by others (example, Cassandrini_2013, Matricardi_2019, Nishri_2016). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although the equivalent mutation in Saccharomyces cerevisiae has been shwon to completely abolish respiration (Cassandrini_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22569581, 33926074, 31102535, 26970947). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=3; Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002500978 SCV002804967 likely pathogenic Pontocerebellar hypoplasia type 6 2022-02-24 criteria provided, single submitter clinical testing
Invitae RCV000757711 SCV003439905 pathogenic not provided 2023-06-29 criteria provided, single submitter clinical testing 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 RARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 618855). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 22569581). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 469 of the RARS2 protein (p.Arg469His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg469 amino acid residue in RARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RARS2 function (PMID: 22569581).
Baylor Genetics RCV002500978 SCV004208425 likely pathogenic Pontocerebellar hypoplasia type 6 2023-08-24 criteria provided, single submitter clinical testing

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