ClinVar Miner

Submissions for variant NM_020320.5(RARS2):c.1A>T (p.Met1Leu)

dbSNP: rs774923951
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centogene AG - the Rare Disease Company RCV001251132 SCV001426630 pathogenic Pontocerebellar hypoplasia type 6 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001310929 SCV001500919 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001310929 SCV002064542 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing DNA sequence analysis of the RARS2 gene demonstrated a sequence change, c.1A>T, in the first exon which is predicted to affect the translation initiation codon p.Met1. This sequence change has been described in the gnomAD database with a low population frequency of 0.00081% (dbSNP rs774923951). This particular amino acid change does not appear to have been described in the literature in other patients with RARS2 related disorders, however, a different pathogenic sequence change affecting the same amino acid residue (p.Met1Val) has been described in the compound heterozygous state in two siblings with pontocerebellar hypoplasia type 6 (PCH6) with some additional symptoms such as cardiomyopathy, hydrops, and pulmonary hypoplasia (PMID: 26083569).
Labcorp Genetics (formerly Invitae), Labcorp RCV001310929 SCV002229817 pathogenic not provided 2025-01-12 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 0.003%). Disruption of the initiator codon has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26083569, 32860008). 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: 974848). This variant disrupts a region of the RARS2 protein in which other variant(s) (p.Ile9Val) have been observed in individuals with RARS2-related conditions (PMID: 22569581). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001310929 SCV002552974 pathogenic not provided 2022-01-06 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32860008, 26795593)
MGZ Medical Genetics Center RCV001251132 SCV002580228 likely pathogenic Pontocerebellar hypoplasia type 6 2021-10-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001251132 SCV002790015 pathogenic Pontocerebellar hypoplasia type 6 2022-01-03 criteria provided, single submitter clinical testing

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