ClinVar Miner

Submissions for variant NM_020320.5(RARS2):c.1026G>A (p.Met342Ile) (rs34647222)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195456 SCV000252167 uncertain significance not provided 2017-11-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RARS2 gene. The M342I variant has been reported previously in an individual with West syndrome, developmental regression, and cerebral atrophy who had a second RARS2 variant on the opposite allele (Pronicka et al., 2016). Additionally, a different missense variant at the same position (M342V) has been reported in an individual with PCH6 who had a second RARS2 variant identified on the opposite allele (Rankin et al., 2010). The M342I variant is observed in 8/16,220 (0.05%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the M342I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Mendelics RCV000987751 SCV001137193 likely pathogenic Pontocerebellar hypoplasia type 6 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987751 SCV001322648 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.

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