ClinVar Miner

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

dbSNP: rs774923951
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Total submissions: 8
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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

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