Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000410901 | SCV000486749 | likely pathogenic | Sjögren-Larsson syndrome | 2016-08-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001216194 | SCV001387976 | pathogenic | not provided | 2023-04-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 19965611). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH3A2 protein function. ClinVar contains an entry for this variant (Variation ID: 371221). This missense change has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 9829906, 17902024, 31273323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 365 of the ALDH3A2 protein (p.Ser365Leu). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000410901 | SCV004223212 | pathogenic | Sjögren-Larsson syndrome | 2023-11-28 | criteria provided, single submitter | clinical testing | Variant summary: ALDH3A2 c.1094C>T (p.Ser365Leu) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR016161) 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 251160 control chromosomes. c.1094C>T has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (examples, Abdel_2019, Rizzo_1999). 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 about 3% of normal activity in FAA-K1A cells (Rizzo_1999). The following publications have been ascertained in the context of this evaluation (PMID: 31273323, 10577908). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |