ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.551C>T (p.Thr184Met) (rs72547562)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169091 SCV000220275 likely pathogenic Sjögren-Larsson syndrome 2014-04-29 criteria provided, single submitter literature only
GeneDx RCV000427449 SCV000516604 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The T184M missense variant in the ALDH3A2 gene has been reported previously in association with Sjögren-Larsson syndrome (Rizzo et al., 1999; Willemsen et al., 2001). This variant is observed in 6/126,726 alleles (0.005%) from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The T184M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, and in vitro studies confirm that the T184M variant is associated with <1% residual enzyme activity (Rizzo et al., 1999). Missense variants in the same codon (T184R) and nearby residues (D179V, G185A) have also been reported in the Human Gene Mutation Database in association with Sjögren-Larsson Syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T184M as a pathogenic variant.
Invitae RCV000427449 SCV000941834 pathogenic not provided 2019-03-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 184 of the ALDH3A2 protein (p.Thr184Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs72547562, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another ALDH3A2 variant in individuals affected with Sjogren-Larsson syndrome (PMID: 10577908, 17998529, 19124283), and has been shown to segregate with disease in a family (PMID: 11408337). ClinVar contains an entry for this variant (Variation ID: 188768). This variant has been reported to affect ALDH3A2 protein function (PMID: 10577908). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169091 SCV001163408 pathogenic Sjögren-Larsson syndrome criteria provided, single submitter clinical testing
Natera, Inc. RCV000169091 SCV001459271 pathogenic Sjögren-Larsson syndrome 2020-09-16 no assertion criteria provided clinical testing

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