Submissions for variant NM_020320.5(RARS2):c.1026G>A (p.Met342Ile)

gnomAD frequency: 0.00014  dbSNP: rs34647222

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195456	SCV000252167	likely pathogenic	not provided	2023-08-31	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34426522, 27290639, 32725632, 34717047, 33798445)
Mendelics	RCV000987751	SCV001137193	likely pathogenic	Pontocerebellar hypoplasia type 6	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987751	SCV001322648	uncertain significance	Pontocerebellar hypoplasia type 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290636	SCV001478753	likely pathogenic	Pontoneocerebellar hypoplasia	2021-01-28	criteria provided, single submitter	clinical testing	Variant summary: RARS2 c.1026G>A (p.Met342Ile) results in a conservative amino acid change located in the Arginyl t-RNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function, however, these outcomes are an unreliable predictor of the associated molecular outcome. A different variant at the same codon, namely, c.1024G>A (p.Met342Val) has been reported as causative of Pontocerebellar hypoplasia in the HGMD database, supporting the possibility of functional relevance of the Methionine 342 residue. The variant allele was found at a frequency of 0.00026 in 250674 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RARS2 causing Pontocerebellar Hypoplasia, Type 6 (0.00026 vs 0.0011), allowing no conclusion about variant significance. c.1026G>A has been reported in the literature in at-least two well genotyped and extensively phenotyped affected individuals who underwent whole exome sequencing (WES) analysis following a history of routine genetic testing that failed to identify the underlying molecular defects (example, Pronicka_2016, Minardi_2020). Both these indidivuals had reported features overlapping mitochondrial disorders and/or Pontocerebellar hypoplasia Type 6. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000987751	SCV001526807	pathogenic	Pontocerebellar hypoplasia type 6	2024-03-23	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000987751	SCV001736827	uncertain significance	Pontocerebellar hypoplasia type 6	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000987751	SCV001806141	uncertain significance	Pontocerebellar hypoplasia type 6	2021-07-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000987751	SCV002557526	likely pathogenic	Pontocerebellar hypoplasia type 6	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pontocerebellar hypoplasia, type 6 (MIM#611523). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (69 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid changes at the same position have been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tRNA synthetases class I (R) domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Met342Val)) has been reported in a compound heterozygous individual with pontocerebellar hypoplasia (PMID: 20635367). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS but more recently as pathogenic and likely pathogenic (ClinVar), and has been observed in three unrelated, compound heterozygous individuals with mitochondrial disorder, progressive myoclonus or cerebellar signs with tonic seizures (PMID: 33798445, PMID: 27290639, PMID: 32725632). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant segregated in an individual and their affected sibling (PMID: 27290639). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV000195456	SCV003491888	uncertain significance	not provided	2022-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 342 of the RARS2 protein (p.Met342Ile). This variant is present in population databases (rs34647222, gnomAD 0.1%). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy and/or pontocerebellar hypoplasia (PMID: 27290639, 32725632). 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: 215064). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Met342 amino acid residue in RARS2. Other variant(s) that disrupt this residue have been observed in individuals with RARS2-related conditions (PMID: 20635367), which suggests that this may be a clinically significant amino acid residue. 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.
Revvity Omics, Revvity	RCV000987751	SCV003813762	uncertain significance	Pontocerebellar hypoplasia type 6	2022-02-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000987751	SCV001455538	uncertain significance	Pontocerebellar hypoplasia type 6	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000195456	SCV001549634	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000195456	SCV001953240	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000195456	SCV001971053	uncertain significance	not provided		no assertion criteria provided	clinical testing