ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.733G>A (p.Asp245Asn) (rs72547568)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000663418 SCV000786717 pathogenic Sjögren-Larsson syndrome criteria provided, single submitter research The homozygous p.Asp245Asn variant was identified by our study in two individuals with Sjogren-Larsson Syndrome. The p.Asp245Asn variant is believed to be pathogenic based on numberous reports in the literature and databases.
Counsyl RCV000663418 SCV000789733 likely pathogenic Sjögren-Larsson syndrome 2017-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000255515 SCV000322393 pathogenic not provided 2016-05-31 criteria provided, single submitter clinical testing The D245N pathogenic variant in the ALDH3A2 gene has been reported previously in the homozygous state, or as part of a complex allele, in multiple unrelated patients with Sjoegren-Larsson syndrome (SLS) (Rizzo et al., 2009; Willemsen et al., 2001; Sarret et al., 2012). D245N 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. It 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 conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, functional studies have shown that the D245N variant almost completely abolishes the enzymatic activity of the protein (Rizzo et al., 1999).
Invitae RCV000255515 SCV000949868 likely pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 245 of the ALDH3A2 protein (p.Asp245Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs72547568, ExAC 0.001%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with Sjoegren-Larsson syndrome (PMID: 21872273). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been observed in other individuals affected with Sjoegren-Larsson syndrome (PMID: 10577908, 11408337). ClinVar contains an entry for this variant (Variation ID: 265459, 438264). Experimental studies have shown that this missense change has a deleterious effect on protein 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.

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