ClinVar Genomic variation as it relates to human health

Variant summary: RARS2 c.1327T>C (p.Ser443Pro) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251374 control chromosomes. c.1327T>C has been reported in the literature as homozygous and compound heterozygous genotype in individuals reportedly affected with features of infantile-onset myoclonic developmental and epleptic encephalopathy/Neurogenetic disorders with brain malfornations/mitochondorial disorders/a neuroradiological diagnosis of Pontocerebellar Hypoplasia (PCH) (example, Karaca_2015, Legati_2016, Matricardi_2019, Nuovo_2022, de Valles-lanez_2022). 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 clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as Likely Pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 34426522, Ginevrino2019[thesis], 26539891, 34085948, 26968897, 32585800)

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 443 of the RARS2 protein (p.Ser443Pro). This variant is present in population databases (rs775295739, gnomAD 0.02%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26539891). ClinVar contains an entry for this variant (Variation ID: 402195). 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. 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.

The RARS2 c.1327T>C variant is predicted to result in the amino acid substitution p.Ser443Pro. This variant has been reported in the homozygous state in two siblings with Intellectual disability, atrophy of bilateral cerebellum, hypoplastic vermis, seizures (Supp. Figure 1, Table S1A, Karaca et al. 2015. PubMed ID: 26539891). It has also been reported in the compound heterozygous state in an individual with respiratory distress, microcephaly, PMD, epilepsy, and pontocerebellar hypoplasia (Table 1, Legati et al. 2016. PubMed ID: 26968897; Nuovo et al. 2022. PubMed ID: 34085948). It has been reported in the heterozygous state in a presumably healthy individual from the Turkish population (Dataset 4, Kars et al. 2021. PubMed ID: 34426522), as well as in 0.026% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-88228436-A-G). This variant is interpreted as likely pathogenic.

The c.1327T>C (p.S443P) alteration is located in exon 16 (coding exon 16) of the RARS2 gene. This alteration results from a T to C substitution at nucleotide position 1327, causing the serine (S) at amino acid position 443 to be replaced by a proline (P). The c.1327T>C (p.S443P) alteration has been reported homozygous in siblings with features suggestive of pontocerebellar hypoplasia, but the siblings also were reported with a second homozygous alteration in the SNX14 gene that could also explain disease. This alteration was also reported to occur in a patient with pontocerebellar hypoplasia along with a second likely pathogenic alteration affecting the initiation codon; however, phase was not confirmed. The p.S443P alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.