Submissions for variant NM_020320.5(RARS2):c.472_474del (p.Lys158del)

gnomAD frequency: 0.00016  dbSNP: rs757743894

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199643	SCV000252175	likely pathogenic	not provided	2020-03-26	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29434700, 22086604, 25533962, 28534666, 27061686, 31216405)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000199643	SCV000886036	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	The RARS2 c.472_474del; p.Lys158del variant (rs757743894; ClinVar Variation ID: 215072) is reported in the literature in individuals affected with RARS2-related phenotypes (de Valles-Ibanez 2022, Fitzgerald 2015, Glamuzina 2012, Ngoh 2016, Roux 2021). Additionally, this variant was identified in trans to a second pathogenic RARS2 variant and was found to segregate in one family (Ngoh 2016). This variant is found in the general population with an overall allele frequency of 0.01% (35/282,486 alleles) in the Genome Aggregation Database (v2.1.1). This variant deletes a single lysine residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic. References: de Valles-Ibanez G et al. Infantile-onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype. Epilepsia Open. 2022 Mar;7(1):170-180. PMID: 34717047. Fitzgerald TW et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015 Mar 12;519(7542):223-8. PMID: 25533962. Glamuzina et al. Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. J Inherit Metab Dis. 2012 May;35(3):459-67. PMID: 22086604. Ngoh et al. RARS2 mutations in a sibship with infantile spasms. Epilepsia. 2016 May;57(5):e97-e102. PMID: 27061686. Roux CJ et al. Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations. Mol Genet Metab. 2021 Jun;133(2):222-229. PMID: 33972171.
Baylor Genetics	RCV000850512	SCV000992716	pathogenic	Pontocerebellar hypoplasia type 6	2024-03-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199643	SCV001576430	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	This variant, c.472_474del, results in the deletion of 1 amino acid(s) of the RARS2 protein (p.Lys158del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757743894, gnomAD 0.02%). This variant has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 22086604, 27061686, 33972171, 34717047). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215072). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271457	SCV002555978	likely pathogenic	Pontoneocerebellar hypoplasia	2025-01-15	criteria provided, single submitter	clinical testing	Variant summary: RARS2 c.472_474delAAA (p.Lys158del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00013 in 251110 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RARS2 causing Pontocerebellar Hypoplasia, Type 6 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.472_474delAAA has been reported in the literature in individuals affected with Pontocerebellar Hypoplasia, Type 6 (e.g. Glamuzina_2012, Ngoh_2016, Roux_2021) and in an individual with early-infantile developmental and epileptic encephalopathy, with signs of cerebellar involvement (de Valles-Ibanez_2022). In at least one family the variant was reported in trans with a pathogenic variant, and was noted to segregate with the phenotype (Ngoh_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22086604, 31216405, 27061686, 33972171, 35707589, 35468344, 34717047). ClinVar contains an entry for this variant (Variation ID: 215072). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000850512	SCV003813880	pathogenic	Pontocerebellar hypoplasia type 6	2023-10-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000850512	SCV005674064	likely pathogenic	Pontocerebellar hypoplasia type 6	2024-04-09	criteria provided, single submitter	clinical testing