VCV000265039.38 - ClinVar

NM_001139.3(ALOX12B):c.1790C>A (p.Ala597Glu)

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.

(6)

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_001139.3(ALOX12B):c.1790C>A (p.Ala597Glu)

Variation ID: 265039 Accession: VCV000265039.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 8073284 (GRCh38) [ NCBI UCSC ] 17: 7976602 (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	Oct 10, 2016	Oct 20, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001139.3:c.1790C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001130.1:p.Ala597Glu	missense
NC_000017.11:g.8073284G>T
NC_000017.10:g.7976602G>T
NG_007099.2:g.19433C>A
LRG_1264:g.19433C>A
LRG_1264t1:c.1790C>A	LRG_1264p1:p.Ala597Glu
	O75342:p.Ala597Glu

... more HGVS ... less HGVS

Protein change

A597E

Other names

Canonical SPDI

NC_000017.11:8073283:G:T

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.

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

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00005

Links

ClinGen: CA8367177 UniProtKB: O75342#VAR_069558 dbSNP: rs752509098 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.
ALOX12B		-	-	GRCh38 GRCh37	309	366

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.
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000255637.28
Autosomal recessive congenital ichthyosis 2	Likely pathogenic (2)	criteria provided, single submitter	-	RCV001289939.4
Lamellar ichthyosis	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV003155138.3

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 (Aug 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321402.8 First in ClinVar: Oct 10, 2016 Last updated: Aug 24, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29444371, 27025581, 31168818, 19890349, 33435499, 31046801, 29687370) (less)
Pathogenic (Apr 29, 2023)	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: SCV003260745.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 19890349‚ 31168818‚ 33435499 Comment: 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) … (more) 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 ALOX12B protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265039). This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 19890349, 31168818, 33435499; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs752509098, gnomAD 0.008%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 597 of the ALOX12B protein (p.Ala597Glu). (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Lamellar ichthyosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003844620.2 First in ClinVar: Mar 26, 2023 Last updated: Jun 29, 2024	Publications: PubMed (4) PubMed: 19890349‚ 33435499‚ 31168818‚ 29687370 Comment: Variant summary: ALOX12B c.1790C>A (p.Ala597Glu) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain of the encoded protein sequence. Four of … (more) Variant summary: ALOX12B c.1790C>A (p.Ala597Glu) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251456 control chromosomes (gnomAD). c.1790C>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (e.g. Valquist_2010, Volozonoka_2018, Simpson_2020, Hotz_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33435499, 31168818, 19890349, 29687370). ClinVar contains an entry for this variant (Variation ID: 265039). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248906.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive congenital ichthyosis 2 Affected status: yes Allele origin: biparental	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004015131.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: DOI: 10.1038/jid.2009.346 DOI: 10.1038/jid.2009.346
Pathogenic (Jan 07, 2021)	no assertion criteria provided Method: clinical testing	Autosomal recessive congenital ichthyosis 2 Affected status: yes Allele origin: unknown	Institute for Human Genetics, University Medical Center Freiburg Accession: SCV001477943.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (1) PubMed: 19890349

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29444371, 27025581, 31168818, 19890349, 33435499, 31046801, 29687370)

Comment:

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 ALOX12B protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265039). This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 19890349, 31168818, 33435499; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs752509098, gnomAD 0.008%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 597 of the ALOX12B protein (p.Ala597Glu).

Comment:

Variant summary: ALOX12B c.1790C>A (p.Ala597Glu) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251456 control chromosomes (gnomAD). c.1790C>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (e.g. Valquist_2010, Volozonoka_2018, Simpson_2020, Hotz_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33435499, 31168818, 19890349, 29687370). ClinVar contains an entry for this variant (Variation ID: 265039). Based on the evidence outlined above, the variant was 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
Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.	Hotz A	Genes	2021	PMID: 33435499
Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.	Simpson JK	The British journal of dermatology	2020	PMID: 31168818
Performance comparison of two whole genome amplification techniques in frame of multifactor preimplantation genetic testing.	Volozonoka L	Journal of assisted reproduction and genetics	2018	PMID: 29687370
Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients.	Vahlquist A	The Journal of investigative dermatology	2010	PMID: 19890349
-	-	-	-	DOI: 10.1038/jid.2009.346

Text-mined citations for rs752509098 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001139.3(ALOX12B):c.1790C>A (p.Ala597Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs752509098 ...