ClinVar Miner

Submissions for variant NM_020320.5(RARS2):c.754T>A (p.Tyr252Asn)

gnomAD frequency: 0.00018  dbSNP: rs140692271
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000372032 SCV000465747 uncertain significance Pontocerebellar hypoplasia type 6 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago RCV000501102 SCV000596720 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing
GeneDx RCV001723960 SCV002520081 uncertain significance not provided 2022-05-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000372032 SCV002768047 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.754T>A in exon 9 of 20 of the RARS2 gene. This substitution is predicted to create a major amino acid change from tyrosine to asparagine at position 252 of the protein, NP_064716.2(RARS2):p.(Tyr252Asn). The tyrosine at this position has very high conservation (100 vertebrates, UCSC), and is located within the tRNA synthetases class I (R) domain. In silico software predicts this variant to be pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at frequencies of 0.03% (38 heterozygotes, 0 homozygotes) in the non-Finnish European population and 0.02% (59 heterozygotes, 0 homozygotes) in the global population. It has been previously reported as a variant of uncertain significance (VUS) in clinical cases (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE.
Labcorp Genetics (formerly Invitae), Labcorp RCV001723960 SCV003247505 uncertain significance not provided 2022-05-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 252 of the RARS2 protein (p.Tyr252Asn). This variant is present in population databases (rs140692271, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 358236). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RARS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001723960 SCV001953156 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001723960 SCV001966196 uncertain significance not provided no assertion criteria provided clinical testing

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