Submissions for variant NM_173076.3(ABCA12):c.4540C>T (p.Arg1514Cys)

dbSNP: rs1266760446

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion, Medical Genetics	RCV002052258	SCV002318862	uncertain significance	Autosomal recessive congenital ichthyosis 4A	2022-03-22	criteria provided, single submitter	clinical testing	The variant is absent from the gnomAD v2.1.1 dataset. Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (ClinVar ID: VCV000002857, PMID:30600594,12915478). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.863>=0.6, 3CNET: 0.968>=0.75). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003773526	SCV004613637	pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1514 of the ABCA12 protein (p.Arg1514Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital ichthyosis (PMID: 36980989). ClinVar contains an entry for this variant (Variation ID: 1526238). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg1514 amino acid residue in ABCA12. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 36980989). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801139	SCV005422727	pathogenic	Lamellar ichthyosis	2024-10-18	criteria provided, single submitter	clinical testing	Variant summary: ABCA12 c.4540C>T (p.Arg1514Cys) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251174 control chromosomes. c.4540C>T has been reported in the literature in individuals affected with Lamellar Ichthyosis and related conditions (Hotz_2023). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.4541G>A, p.Arg1514His), supporting the critical relevance of codon 1514 to ABCA12 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36980989). ClinVar contains an entry for this variant (Variation ID: 1526238). Based on the evidence outlined above, the variant was classified as pathogenic.