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

dbSNP: rs72547567

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Invitae	RCV001377682	SCV001575075	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 237 of the ALDH3A2 protein (p.Cys237Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Sjögren-Larsson syndrome (PMID: 10577908, 16903323, 20049467). ClinVar contains an entry for this variant (Variation ID: 631767). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 10577908). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.