Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001382953 | SCV001581914 | pathogenic | not provided | 2023-08-28 | criteria provided, single submitter | clinical testing | Disruption of the initiator codon has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26083569). It has also been observed to segregate with disease in related individuals. This sequence change affects the initiator methionine of the RARS2 mRNA. The next in-frame methionine is located at codon 176. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1070705). This variant disrupts a region of the RARS2 protein in which other variant(s) (p.Gln12Arg) have been determined to be pathogenic (PMID: 20635367, 20952379, 22569581). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797837 | SCV002041760 | pathogenic | Pontoneocerebellar hypoplasia | 2021-11-16 | criteria provided, single submitter | clinical testing | Variant summary: RARS2 c.3G>A (p.Met1Ile) alters the initiation codon and an alternative downstream in-frame start codon (Met176) is located in exon 7 of the encoded protein. It is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250948 control chromosomes (gnomAD). c.3G>A has been reported in the literature in at least one individual affected with prominent progressive action myoclonus (Courage_2021). Additionally, different variants (c.1A>T, c.1A>G) with disruption of this start codon were found in patients affected with Pontocerebellar hypoplasia (Lax_2015, Farwell_2015, Hou_2020, Bertoli-Avella_2021) and classified as pathogenic in ClinVar database. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |