ClinVar Genomic variation as it relates to human health
NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs)
Variation ID: 1641 Accession: VCV000001641.22
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 17p11.2 17: 19671805-19671806 (GRCh38) [ NCBI UCSC ] 17: 19575118-19575119 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 9, 2017 Feb 20, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000382.3:c.1297_1298del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000373.1:p.Glu433fs frameshift NM_000382.3:c.1297_1298delGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000382.2:c.1297_1298del NM_001031806.2:c.1297_1298del NP_001026976.1:p.Glu433fs frameshift NM_001369136.1:c.1297_1298del NP_001356065.1:p.Glu433fs frameshift NM_001369137.2:c.1297_1298del NP_001356066.1:p.Glu433fs frameshift NM_001369138.2:c.1297_1298del NP_001356067.1:p.Glu433fs frameshift NM_001369139.1:c.1297_1298del NP_001356068.1:p.Glu433fs frameshift NM_001369146.2:c.1208-3753AG[2] intron variant NM_001369148.2:c.718_719del NP_001356077.1:p.Glu240fs frameshift NC_000017.11:g.19671806GA[2] NC_000017.10:g.19575119GA[2] NG_007095.2:g.28056GA[2] - Protein change
- E240fs, E433fs
- Other names
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- Canonical SPDI
- NC_000017.11:19671804:AGAGAGA:AGAGA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ALDH3A2 | - | - |
GRCh38 GRCh37 |
- | 752 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000001708.12 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000413153.16 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490399.2
First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916433.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806279.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041276.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001211465.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 01, 1999)
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no assertion criteria provided
Method: literature only
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SJOGREN-LARSSON SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021864.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 20, 2017 |
Comment on evidence:
In a patient with Sjogren-Larsson syndrome (SLS; 270200), Tsukamoto et al. (1997) found a 2-bp deletion (1297_1298delGA) of the ALDH10 gene, with consequent premature chain … (more)
In a patient with Sjogren-Larsson syndrome (SLS; 270200), Tsukamoto et al. (1997) found a 2-bp deletion (1297_1298delGA) of the ALDH10 gene, with consequent premature chain termination at protein position 434. In a study of 29 SLS patients with biochemically defined FALDH deficiency in the Netherlands, IJlst et al. (1999) found an allele frequency of 10/58 (17.2%) for the 1297-1298delGA allele. (less)
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Likely pathogenic
(Mar 10, 2016)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802410.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742833.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001463379.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808066.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969660.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV000986929.1
First in ClinVar: Aug 30, 2019 Last updated: Aug 30, 2019 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta … (more)
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta (present) , Maternal teratogenic exposure (present) , Premature birth (present) , Abnormality of the umbilical cord (present) , Overgrowth (present) , Obesity (present) , Tall stature (present) , Abnormality of the ear (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Anxiety (present) , Depressivity (present) , Short attention span (present) , Joint hypermobility (present) , Abnormality of muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Asthma (present) , Abnormal pattern of respiration (present) , Abnormality of the male genitalia (present) , Recurrent infections (present) , Misalignment of teeth (present) (less)
Age: 20-29 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-07-26
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Ichthyosis in Sjögren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion. | Rizzo WB | Archives of dermatological research | 2010 | PMID: 20049467 |
Sjögren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. | Rizzo WB | Molecular genetics and metabolism | 2007 | PMID: 16996289 |
Bezafibrate induces FALDH in human fibroblasts; implications for Sjögren-Larsson syndrome. | Gloerich J | Molecular genetics and metabolism | 2006 | PMID: 16837225 |
RNA-based mutation screening in German families with Sjögren-Larsson syndrome. | Kraus C | European journal of human genetics : EJHG | 2000 | PMID: 10854114 |
The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. | Rizzo WB | American journal of human genetics | 1999 | PMID: 10577908 |
Molecular basis of Sjögren-Larsson syndrome: frequency of the 1297-1298 del GA and 943C-->T mutation in 29 patients. | Ijlst L | Journal of inherited metabolic disease | 1999 | PMID: 10384396 |
Mutations associated with Sjögren-Larsson syndrome. | Tsukamoto N | Annals of human genetics | 1997 | PMID: 9250352 |
Text-mined citations for rs387906256 ...
HelpRecord last updated Jun 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.