Submissions for variant NM_173076.3(ABCA12):c.485C>T (p.Ala162Val)

gnomAD frequency: 0.00126  dbSNP: rs149399707

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224053	SCV000281280	uncertain significance	not provided	2015-09-15	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Illumina Laboratory Services, Illumina	RCV000300752	SCV000427323	uncertain significance	Congenital ichthyosis of skin	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000224053	SCV000620787	uncertain significance	not provided	2017-09-19	criteria provided, single submitter	clinical testing	The A162V variant in the ABCA12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, it is reported as a variant of uncertain significance in ClinVar by two different clinical laboratories, but additional evidence is not available (ClinVar SCV000281280.1 and SCV000427323.2; Landrum et al., 2016). The A162V variant is observed in 124/66,462 alleles (0.19%) from individuals of non-Finnish European background in the ExAC dataset, including one homozygous control individual (Lek et al., 2016). The A162V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A162V as a variant of uncertain significance.
Invitae	RCV000224053	SCV001051120	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265699	SCV002547715	benign	not specified	2022-05-03	criteria provided, single submitter	clinical testing	Variant summary: ABCA12 c.485C>T (p.Ala162Val) results in a non-conservative amino acid change in 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 0.0014 in 250822 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA12 causing Lamellar Ichthyosis phenotype (0.00066), strongly suggesting that the variant is benign. To our knowledge, no penetrant association c.485C>T in individuals affected with Lamellar Ichthyosis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000224053	SCV004042118	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ABCA12: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003907839	SCV004722839	likely benign	ABCA12-related disorder	2022-02-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).