Submissions for variant NM_020320.5(RARS2):c.1A>G (p.Met1Val)

dbSNP: rs774923951

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210553	SCV000262908	likely pathogenic	Inborn genetic diseases	2024-08-26	criteria provided, single submitter	clinical testing	The c.1A>G (p.M1?) alteration is located in coding exon 1 of the RARS2 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on data from gnomAD, the G allele has an overall frequency of 0.011% (31/282330) total alleles studied. The highest observed frequency was 0.033% (10/30616) of South Asian alleles. This variant has been identified in conjunction with other RARS2 variants in individuals with features consistent with mitochondrial arginyl-tRNA synthetase; in at least one instance, the variants were identified in trans (Farwell, 2015; Lax, 2015; Helbig, 2016; Matricardi, 2019; Weng, 2021; Chuan, 2022; Zhao, 2024). Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx	RCV000657931	SCV000779700	pathogenic	not provided	2024-09-24	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Observed with a second RARS2 variant in patients with features of aminoacyl-tRNA synthetase deficiency in published literature (PMID: 26083569, 25356970, 26795593); This variant is associated with the following publications: (PMID: 34670123, 34085948, 29434700, 26083569, 25356970, 26795593, 25326635, 31980526, 34426522, 31589614, 34247374, 35571021)
Baylor Genetics	RCV000680147	SCV000807594	pathogenic	Pontocerebellar hypoplasia type 6	2017-09-01	criteria provided, single submitter	clinical testing	This initiation codon variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory with another variant in a 13-year-old male with intellectual disability, epilepsy, truncal ataxia, growth retardation. It was also seen once de novo in a 10-month-old female with epilpsy, delays, hypotonia, who also had a de novo pathogenic ATP1A3 variant. Heterozygotes are expected to be asymptomatic carriers.
Fulgent Genetics, Fulgent Genetics	RCV000680147	SCV000894399	pathogenic	Pontocerebellar hypoplasia type 6	2024-06-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657931	SCV001591738	pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the RARS2 mRNA. The next in-frame methionine is located at codon 176. This variant is present in population databases (rs774923951, gnomAD 0.03%). Disruption of the initiator codon has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26083569). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225026). This variant disrupts the p.Gln12 amino acid residue in RARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20635367, 20952379, 22569581). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000680147	SCV002019031	likely pathogenic	Pontocerebellar hypoplasia type 6	2020-01-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000680147	SCV001459660	pathogenic	Pontocerebellar hypoplasia type 6	2020-09-16	no assertion criteria provided	clinical testing
Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University	RCV000680147	SCV003852746	pathogenic	Pontocerebellar hypoplasia type 6		no assertion criteria provided	clinical testing