ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.798G>C (p.Lys266Asn) (rs72547569)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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

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