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

dbSNP: rs781059624

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Mass General Brigham 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.
Invitae	RCV001867905	SCV002242768	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys431Glufs*5) in the ALDH3A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). This variant is present in population databases (rs781059624, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 10577908, 30157790). ClinVar contains an entry for this variant (Variation ID: 495850). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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*).