Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002468977 | SCV002766416 | uncertain significance | not specified | 2024-05-22 | criteria provided, single submitter | clinical testing | Variant summary: RARS2 c.1024A>G (p.Met342Val) results in a conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250688 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1024A>G has been reported in the literature as a compound heterozygous genotype in trans with a pathogenic variant (ClinVar) in at least 1 individual affected with features of Pontocerebellar Hypoplasia, Type 6 who has been subsequently cited by others (example, Rankin_2010, cited in Namavar_2011, Nishri_2016, Ngoh_2016, Aldinger_2019, Nevanlinna_2020). In this individual, despite the absence of respiratory chain defects, the MRI findings and lactic acidosis were felt to be consistent with PCH6 and only the RARS2 gene was analyzed. Further, a different missense variant at the same codon p.Met342Ile has been reported to be LP/P by at least 5 laboratories in ClinVar, supporting the clinical importance of this amino acid residue. These data do not allow firm conclusions about variant significance. In vitro functional analysis found this variant had no effect on protein localization or expression, however function was not assessed (example, Gonzlez-Serrano_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31474318, 30006346, 20952379, 31536827, 27061686, 26970947, 20635367). No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| OMIM | RCV000023898 | SCV000045189 | pathogenic | Pontocerebellar hypoplasia type 6 | 2010-08-01 | no assertion criteria provided | literature only |