ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.1291_1292del (p.Lys431fs)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital,College of Medicine, The Catholic University of Korea RCV000588137 SCV000882773 pathogenic Sjögren-Larsson syndrome 2019-02-11 no assertion criteria provided research The proband has another variant, NM_000382.2: c.1309A>T (p.Lys437*).
Integrated Genetics/Laboratory Corporation of America RCV000588137 SCV000696646 pathogenic Sjögren-Larsson syndrome 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The ALDH3A2 c.1291_1292delAA (p.Lys431Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent ALDH3A2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121534 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDH3A2 variant (0.0017889). This variant has been reported in multiple SLS pts as homozygote or compound heterozygotes. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000588137 SCV000967007 pathogenic Sjögren-Larsson syndrome 2018-09-21 criteria provided, single submitter clinical testing The p.Lys431GlufsX5 variant in ALDH3A2 has been reported in the homozygous or co mpound heterozygous state in 2 Japanese individuals with Sjogren-Larsson syndrom e and segregated with disease in 1 affected family member (Rizzo 1999, Takeichi 2013 ). It has also been identified in 1/17248 of East Asian chromosomes by gnom AD (http://gnomad.broadinstitute.org). This variant has also been reported in Cl inVar (Variation ID 495850). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 431 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ALDH3A2 gene is an established disease mechanism in Sjogren-Larsson syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Sjogren-Larsson syndrome based on case observations, segregation studies, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PM2, PM 3, PP1.

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