VCV000002855.13 - ClinVar

NM_173076.3(ABCA12):c.4139A>G (p.Asn1380Ser)

Germline

Classification

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.

(8)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_173076.3(ABCA12):c.4139A>G (p.Asn1380Ser)

Variation ID: 2855 Accession: VCV000002855.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214986566 (GRCh38) [ NCBI UCSC ] 2: 215851290 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 25, 2015	Jul 23, 2024	Jan 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_173076.3:c.4139A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_775099.2:p.Asn1380Ser	missense
NM_015657.4:c.3185A>G	NP_056472.2:p.Asn1062Ser	missense
NR_103740.2:n.4637A>G		non-coding transcript variant
NC_000002.12:g.214986566T>C
NC_000002.11:g.215851290T>C
NG_007074.1:g.156862A>G
	Q86UK0:p.Asn1380Ser

... more HGVS ... less HGVS

Protein change

N1380S, N1062S

Other names

Canonical SPDI

NC_000002.12:214986565:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00007

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA252475 UniProtKB: Q86UK0#VAR_019598 OMIM: 607800.0002 dbSNP: rs28940269 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
ABCA12		-	-	GRCh38 GRCh37	1119	1531

Conditions - Germline

Condition Help 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 Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive congenital ichthyosis 4A	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV000002989.7
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 27, 2024	RCV000255645.9
Autosomal recessive congenital ichthyosis 4A Autosomal recessive congenital ichthyosis 4B	Likely pathogenic (1)	criteria provided, single submitter	May 14, 2022	RCV000763068.3

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.
Likely pathogenic (May 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive congenital ichthyosis 4B Autosomal recessive congenital ichthyosis 4A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893574.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Apr 09, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321322.8 First in ClinVar: Oct 09, 2016 Last updated: Apr 15, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20672373, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20672373, 29630152, 27025581, 29722424, 30530421, 10094194, 8845852, 21729033, 12915478, 31168818, 32851342, 30916489, 29887490, 32069299, 36980989) (less)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive congenital ichthyosis 4A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557620.2 First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 30916489‚ 32851342 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital ichthyosis 4A (MIM#601277) and congenital ichthyosis 4B (harlequin) (MIM#242500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 1 domain (Decipher). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in compound heterozygous and homozygous states in multiple individuals with congenital ichthyosis (ClinVar, PMID: 30916489, 32851342). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive congenital ichthyosis 4A Affected status: yes Allele origin: germline	3billion Accession: SCV002521606.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (3) PubMed: 30916489‚ 29887490‚ 29722424 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). In silico tool predictions suggest damaging effect … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.82). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002855). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:29722424, 30916489). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 29722424, 29887490, 30916489). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Decreased body weight (present) , Hypoglycemia (present) , Exocrine pancreatic insufficiency (present) , Hashimoto thyroiditis (present) , Generalized ichthyosis (present) , Short stature (present)
Pathogenic (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004264705.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 12915478‚ 31168818‚ 32851342 Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1380 of the ABCA12 protein (p.Asn1380Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1380 of the ABCA12 protein (p.Asn1380Ser). This variant is present in population databases (rs28940269, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 12915478, 31168818, 32851342). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA12 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 15, 2003)	no assertion criteria provided Method: literature only	ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 4A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023147.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 25, 2015	Publications: PubMed (3) PubMed: 8845852‚ 10094194‚ 12915478 Comment on evidence: In 3 affected individuals from 3 consanguineous Moroccan families with congenital ichthyosis (ARCI4A; 601277) of the lamellar type, 1 of which was originally reported by … (more) In 3 affected individuals from 3 consanguineous Moroccan families with congenital ichthyosis (ARCI4A; 601277) of the lamellar type, 1 of which was originally reported by Parmentier et al. (1996) and 2 of which were previously studied by Parmentier et al. (1999), as well as a similarly affected individual from a consanguineous Algerian family, Lefevre et al. (2003) identified homozygosity for a 4139A-G transition in the ABCA12 gene. The mutation was predicted to result in an asn1380-to-ser (N1380S) substitution in the nucleotide-binding fold (NBF1) domain. In 3 sibs with lamellar ARCI from a nonconsanguineous Algerian family, previously studied by Parmentier et al. (1999), Lefevre et al. (2003) identified compound heterozygosity for the N1380S mutation and another ABCA12 missense mutation, G1651S (607800.0003). Neither mutation was found in 100 North African control chromosomes. A common haplotype was found in 4 of the 5 families carrying the N1380S mutation, including 2 of the Moroccan families and both Algerian families, suggesting a founder effect. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951563.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001966105.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20672373, 29630152, 27025581, 29722424, 30530421, 10094194, 8845852, 21729033, 12915478, 31168818, 32851342, 30916489, 29887490, 32069299, 36980989)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital ichthyosis 4A (MIM#601277) and congenital ichthyosis 4B (harlequin) (MIM#242500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 1 domain (Decipher). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in compound heterozygous and homozygous states in multiple individuals with congenital ichthyosis (ClinVar, PMID: 30916489, 32851342). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.82). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002855). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:29722424, 30916489). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 29722424, 29887490, 30916489). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1380 of the ABCA12 protein (p.Asn1380Ser). This variant is present in population databases (rs28940269, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 12915478, 31168818, 32851342). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA12 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital ichthyosiform erythroderma with a novel variant in ABCA12 in a Chinese patient.	Yang Z	Pediatric investigation	2020	PMID: 32851342
Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.	Simpson JK	The British journal of dermatology	2020	PMID: 31168818
A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype-phenotype correlations.	Montalván-Suárez M	Molecular genetics & genomic medicine	2019	PMID: 30916489
ABCA12 mutations in patients with autosomal recessive congenital ichthyosis: evidence of a founder effect in the Spanish population and phenotype-genotype implications.	Esperón-Moldes U	Journal of dermatological science	2018	PMID: 29887490
Hearing impairment: A secondary symptom in a congenital ichthyosiform erythroderma patient with ABCA12 mutations.	Murase C	The Journal of dermatology	2018	PMID: 29722424
Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2.	Lefévre C	Human molecular genetics	2003	PMID: 12915478
Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus.	Parmentier L	European journal of human genetics : EJHG	1999	PMID: 10094194
Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-35.	Parmentier L	Human molecular genetics	1996	PMID: 8845852

Text-mined citations for rs28940269 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_173076.3(ABCA12):c.4139A>G (p.Asn1380Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28940269 ...