ClinVar Genomic variation as it relates to human health
NM_173076.3(ABCA12):c.7444C>T (p.Arg2482Ter)
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_173076.3(ABCA12):c.7444C>T (p.Arg2482Ter)
Variation ID: 419453 Accession: VCV000419453.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 214937608 (GRCh38) [ NCBI UCSC ] 2: 215802332 (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 Apr 27, 2017 Feb 14, 2024 Oct 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_173076.3:c.7444C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_775099.2:p.Arg2482Ter nonsense NM_015657.4:c.6490C>T NP_056472.2:p.Arg2164Ter nonsense NR_103740.2:n.7942C>T non-coding transcript variant NC_000002.12:g.214937608G>A NC_000002.11:g.215802332G>A NG_007074.1:g.205820C>T - Protein change
- R2482*, R2164*
- Other names
- p.Arg2482Ter
- Canonical SPDI
- NC_000002.12:214937607:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- unknown functional consequence
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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
Help
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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ABCA12 | - | - |
GRCh38 GRCh37 |
1110 | 1519 | |
SNHG31 | - | - | - | GRCh38 | - | 389 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 15, 2023 | RCV000480311.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 15, 2022 | RCV000677681.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2022 | RCV002231097.1 |
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
(Aug 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 4B
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803824.1 First in ClinVar: Aug 25, 2018 Last updated: Aug 25, 2018 |
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Pathogenic
(Jul 05, 2018)
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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: SCV000567262.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
The R2482X pathogenic variant in the ABCA12 gene has been reported previously with another ABCA12 variant in association with harlequin ichthyosis (Akiyama et al., 2007; … (more)
The R2482X pathogenic variant in the ABCA12 gene has been reported previously with another ABCA12 variant in association with harlequin ichthyosis (Akiyama et al., 2007; Koocheck et al., 2014). In one of these patients, immunostaining of a skin biopsy demonstrated complete loss of ABCA12 expression in the epidermis (Akiyama et al., 2007). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R2482X variant is observed in 1/9,838 (0.01%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). We interpret R2482X as a pathogenic variant. (less)
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Pathogenic
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lamellar ichthyosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511983.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: ABCA12 c.7444C>T (p.Arg2482X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ABCA12 c.7444C>T (p.Arg2482X) 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 2e-05 in 250934 control chromosomes. c.7444C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with features of Lamellar Ichthyosis/Harlequin Ichthyosis (example, Sakai_2009, Khalili_2019, Cho_2017, Kun-Darbois_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 4B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002764607.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A homozygous nonsense variation in exon 51 of the ABCA12 gene that results in a stop codon and premature truncation of the protein at codon … (more)
A homozygous nonsense variation in exon 51 of the ABCA12 gene that results in a stop codon and premature truncation of the protein at codon 2482 was detected. The observed variation has previously been reported in patients with Herlequin ichthyosis (PMID:17684380). The variant has a minor allele frequency of 0.02% in the 1000 genomes database. The reference region is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Harlequin phenomenon (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Oct 15, 2023)
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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: SCV003524973.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg2482*) in the ABCA12 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg2482*) in the ABCA12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA12 are known to be pathogenic (PMID: 20672373). This variant is present in population databases (rs199503269, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital ichthyosis (PMID: 17684380, 28851938, 31168818). ClinVar contains an entry for this variant (Variation ID: 419453). For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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unknown functional consequence
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002764607.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis. | Simpson JK | The British journal of dermatology | 2020 | PMID: 31168818 |
Management of ocular manifestations of autosomal recessive congenital ichthyosis 4B, harlequin type, in the perinatal period. | Khalili A | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2019 | PMID: 31586585 |
Prevalence of Rare Genetic Variations and Their Implications in NGS-data Interpretation. | Cho Y | Scientific reports | 2017 | PMID: 28851938 |
Facial features in Harlequin ichthyosis: Clinical findings about 4 cases. | Kün-Darbois JD | Revue de stomatologie, de chirurgie maxillo-faciale et de chirurgie orale | 2016 | PMID: 26740202 |
ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. | Akiyama M | Human mutation | 2010 | PMID: 20672373 |
ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma. | Sakai K | The Journal of investigative dermatology | 2009 | PMID: 19262603 |
Compound heterozygous ABCA12 mutations including a novel nonsense mutation underlie harlequin ichthyosis. | Akiyama M | Dermatology (Basel, Switzerland) | 2007 | PMID: 17684380 |
Text-mined citations for rs199503269 ...
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.