Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414702 | SCV000490987 | likely pathogenic | not provided | 2016-06-14 | criteria provided, single submitter | clinical testing | The K266N variant in the ALDH3A2 gene has been reported previously in patients with Sjogren-Larsson syndrome (SLS) (Rizzo et al., 1999; Willemsen et al., 2001). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K266N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, several splice prediction models predict that this variant destroys the natural splice donor site in intron 5. Therefore, the K266N variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Labcorp Genetics |
RCV000414702 | SCV001582571 | pathogenic | not provided | 2023-01-30 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that this missense change alters ALDH3A2 gene expression (PMID: 10577908). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1643). This missense change has been observed in individuals with Sjögren-Larsson syndrome (PMID: 11408337, 17971613). This variant is present in population databases (rs72547569, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 266 of the ALDH3A2 protein (p.Lys266Asn). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. |
| OMIM | RCV000001710 | SCV000021866 | pathogenic | Sjögren-Larsson syndrome | 1999-12-01 | no assertion criteria provided | literature only |