ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs) (rs387906256)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413153 SCV000490399 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The c.1297_1298delGA variant in the ALDH3A2 gene has been reported previously as the most common pathogenic variant observed among Sjögren-Larsson syndrome patients of European heritage (Tsukamoto et al., 1997; Ijlst et al., 1999; Rizzo et al., 2005). This variant causes a frameshift starting with codon Glutamic acid 433, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Glu433ArgfsX3. The c.1297_1298delGA variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and is associated with <1% residual enzyme activity (Rizzo et al., 2005). This variant is observed in 9/126,722 alleles (0.007%) from individuals of non-Finnish European background, with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). We interpret c.1297_1298delGA as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001708 SCV000916433 pathogenic Sjögren-Larsson syndrome 2018-10-11 criteria provided, single submitter clinical testing Variant summary: ALDH3A2 c.1297_1298delGA (p.Glu433ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-05 in 277238 control chromosomes (gnomAD). c.1297_1298delGA has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (Gloerich_2006, Rizzo_2010) and patients were found to have significantly reduced FADH activity (<10%; Gloerich_2006). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000413153 SCV001211465 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu433Argfs*3) in the ALDH3A2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs756844187, ExAC 0.004%). This variant has been reported to segregate with Sjogren-Larsson syndrome (SLS) in many individuals (PMID: 9250352, 20049467, 16996289). ClinVar contains an entry for this variant (Variation ID: 1641). Loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001708 SCV000021864 pathogenic Sjögren-Larsson syndrome 1999-05-01 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000413153 SCV000802410 likely pathogenic not provided 2016-03-10 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000001708 SCV000986929 not provided Sjögren-Larsson syndrome no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc. RCV000001708 SCV001463379 pathogenic Sjögren-Larsson syndrome 2020-09-16 no assertion criteria provided clinical testing

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