ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.710G>A (p.Cys237Tyr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778493 SCV000914757 likely pathogenic Sjögren-Larsson syndrome 2017-08-29 criteria provided, single submitter clinical testing The ALDH3A2 c.710G>A (p.Cys237Tyr) missense variant has been reported in one study and identified in two unrelated homozygous individuals with Sjögren-Larrson syndrome (Rizzo et al. 1999). Control data are unavailable for this variant. The p.Cys237Tyr variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Rizzo et al. (1999) used Chinese hamster ovary cells to determine the FALDH activity for the variant and it was found to be <1% of wild type. Keller et al. (2014) identified the p.Cys237Tyr variant as one that likely destabilizes the FALDH protein fold by changing the polarity or the size of the side chain. Based on the evidence, the p.Cys237Tyr variant is classified as likely pathogenic for Sjögren-Larrson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000778493 SCV000918411 pathogenic Sjögren-Larsson syndrome 2018-06-28 criteria provided, single submitter clinical testing Variant summary: ALDH3A2 c.710G>A (p.Cys237Tyr) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246236 control chromosomes (gnomAD). The variant, c.710G>A, has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (Alio_2006, Rizzo_1999, Hidalgo_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 10% of normal activity (Rizzo_1999). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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