rs387906256
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000382.3(ALDH3A2):c.1297_1298delGA(p.Glu433ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
ALDH3A2
NM_000382.3 frameshift
NM_000382.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.44
Genes affected
ALDH3A2 (HGNC:403): (aldehyde dehydrogenase 3 family member A2) Aldehyde dehydrogenase isozymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This gene product catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. Mutations in the gene cause Sjogren-Larsson syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-19671804-AAG-A is Pathogenic according to our data. Variant chr17-19671804-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 1641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19671804-AAG-A is described in Lovd as [Pathogenic]. Variant chr17-19671804-AAG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251470Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135910
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GnomAD4 exome AF: 0.000103 AC: 150AN: 1461882Hom.: 0 AF XY: 0.0000949 AC XY: 69AN XY: 727242
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GnomAD4 genome 0.0000591 AC: 9AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2025 | 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. Loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). This variant is present in population databases (rs756844187, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with Sjogren-Larsson syndrome (SLS) (PMID: 9250352, 16996289, 20049467). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1641). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2019 | 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. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 10, 2016 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Sjögren-Larsson syndrome Pathogenic:5Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1999 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2018 | 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. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 07, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 17, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at