VCV002734378.1 - ClinVar

NM_173076.3(ABCA12):c.3470C>T (p.Ser1157Leu)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_173076.3(ABCA12):c.3470C>T (p.Ser1157Leu)

Variation ID: 2734378 Accession: VCV002734378.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214990856 (GRCh38) [ NCBI UCSC ] 2: 215855580 (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	Feb 14, 2024	Feb 14, 2024	Oct 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_173076.3:c.3470C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_775099.2:p.Ser1157Leu	missense
NM_015657.4:c.2516C>T	NP_056472.2:p.Ser839Leu	missense
NR_103740.2:n.3968C>T		non-coding transcript variant
NC_000002.12:g.214990856G>A
NC_000002.11:g.215855580G>A
NG_007074.1:g.152572C>T
NG_007074.2:g.152770C>T

... more HGVS ... less HGVS

Protein change

S1157L, S839L

Other names

Canonical SPDI

NC_000002.12:214990855:G:A

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.

Links

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	1116	1528

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	Likely pathogenic (1)	criteria provided, single submitter	Oct 26, 2023	RCV003554990.2

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 (Oct 26, 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: SCV004293945.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 25766764‚ 27061915‚ 36980989 Comment: This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1157 of the ABCA12 protein (p.Ser1157Leu). … (more) This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1157 of the ABCA12 protein (p.Ser1157Leu). This variant is present in population databases (rs780940154, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 25766764, 27061915, 36980989). This variant is also known as p.Ser1157Ile. 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)

Comment:

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1157 of the ABCA12 protein (p.Ser1157Leu). This variant is present in population databases (rs780940154, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 25766764, 27061915, 36980989). This variant is also known as p.Ser1157Ile. 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis.	Hotz A	Genes	2023	PMID: 36980989
Novel mutations in TGM1 and ABCA12 cause autosomal recessive congenital ichthyosis in five Saudi families.	Wakil SM	International journal of dermatology	2016	PMID: 27061915
Mutation study for 9 genes in 23 unrelated patients with autosomal recessive congenital ichthyosis in Japan and Malaysia.	Numata S	Journal of dermatological science	2015	PMID: 25766764

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_173076.3(ABCA12):c.3470C>T (p.Ser1157Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...