ClinVar Miner

Submissions for variant NM_020320.5(RARS2):c.25A>G (p.Ile9Val)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470547 SCV002768704 uncertain significance Pontocerebellar hypoplasia type 6 2019-08-28 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_020320.4(RARS2):c.25A>G in exon 1 of 20 of the RARS2 gene. This substitution is predicted to create a minor amino acid change from isoleucine to valine at position 9 of the protein, NP_064716.2(RARS2):p.(Ile9Val). The isoleucine at this position has very high conservation (100 vertebrates, UCSC), and is located within the transit peptide - Mitochondrion functional domain. In silico software predicts this variant to be benign (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.002% (5 heterozygotes, 0 homozygotes). An alternative residue change to threonine at the same location has also been reported in the gnomAD database at a frequency of 0.0004%. The variant has been previously reported in a compound heterozygous state as potentially pathogenic in two siblings with Pontocerebellar hypoplasia (Cassandrini, D. et al. (2013)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE.
Revvity Omics, Revvity RCV002470547 SCV003813766 uncertain significance Pontocerebellar hypoplasia type 6 2021-04-15 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV002470547 SCV004100920 uncertain significance Pontocerebellar hypoplasia type 6 criteria provided, single submitter clinical testing The missense variant p.I9V in RARS2 (NM_020320.5) has been reported previously as one of the compound heterozygous variant in a patient with progressive pontocerebellar and cerebral cortical atrophy (Cassindrini et al, 2012). The p.I9V variant is observed in 3/15,916 (0.0188%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Uncertain Significance.
Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University RCV002470547 SCV003841248 likely pathogenic Pontocerebellar hypoplasia type 6 no assertion criteria provided clinical testing

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