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	2021-03-26	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 the Genome Aggregation Database (gnomAD) database, the RARS2 c.1A>G alteration was observed in 0.01% (31/282330) of total alleles studied, with a frequency of 0.03% (10/30616) in the South Asian subpopulation. No homozygotes were observed. This alteration has been observed to occur in trans with a second alterations in 3 patients from two families with symptoms consistent with mitochondrial arginyl-tRNA synthetase deficiency (Farwell, 2015; Helbig, 2016; Lax, 2015). Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx	RCV000657931	SCV000779700	pathogenic	not provided	2018-12-21	criteria provided, single submitter	clinical testing	The c.1A>G variant in the RARS2 gene has been reported previously in pontocerebellar hypoplasia type 6, in affected individuals who were compound heterozygous for the c.1A>G variant and another variant (Lax et al., 2015; Farwell et al., 2015). As this pathogenic variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. The c.1A>G variant is observed in 9/30782 (0.029%) alleles from individuals of South Asian background, and 29/276974 total alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1A>G as a pathogenic variant.
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	likely pathogenic	Pontocerebellar hypoplasia type 6	2021-07-08	criteria provided, single submitter	clinical testing
Invitae	RCV000657931	SCV001591738	pathogenic	not provided	2024-01-31	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