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. |
| Invitae | RCV000414702 | SCV001582571 | pathogenic | not provided | 2020-07-12 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine with asparagine at codon 266 of the ALDH3A2 protein (p.Lys266Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 5 of the ALDH3A2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs72547569, ExAC 0.002%). This variant has been observed in individual(s) with Sjögren-Larsson syndrome (PMID: 11408337, 17971613). ClinVar contains an entry for this variant (Variation ID: 1643). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10577908). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000001710 | SCV000021866 | pathogenic | Sjögren-Larsson syndrome | 1999-12-01 | no assertion criteria provided | literature only |