Submissions for variant NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)

gnomAD frequency: 0.00001  dbSNP: rs1258569046

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553691	SCV001774650	pathogenic	Pontoneocerebellar hypoplasia	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: RARS2 c.848T>A (p.Leu283Gln) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251248 control chromosomes. c.848T>A has been reported in the literature in multiple individuals affected with Pontocerebellar Hypoplasia, Type 6 or related diseases (e.g. Fitzgerald_2015, Ngoh_2016, Mathew_2018). These data indicate that the variant is very likely to be associated with disease. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000779649	SCV001981597	likely pathogenic	Pontocerebellar hypoplasia type 6		criteria provided, single submitter	clinical testing
Invitae	RCV001869150	SCV002243496	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 283 of the RARS2 protein (p.Leu283Gln). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of pontocerebellar hypoplasia (PMID: 2706168, 25533962, 29881806, 31429931, 31474318). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632596). 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000779649	SCV004208488	likely pathogenic	Pontocerebellar hypoplasia type 6	2021-11-04	criteria provided, single submitter	clinical testing
Dobyns Lab, Seattle Children's Research Institute	RCV000779649	SCV000916328	likely pathogenic	Pontocerebellar hypoplasia type 6	2019-02-18	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001258003	SCV001434816	likely pathogenic	Congenital cerebellar hypoplasia		no assertion criteria provided	research