Submissions for variant NM_173076.3(ABCA12):c.179G>C (p.Arg60Pro)

dbSNP: rs762065937

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256128	SCV000321314	likely pathogenic	not provided	2017-03-30	criteria provided, single submitter	clinical testing	The R60P variant has been reported along with a nonsense variant in a patient with Harlequin ichthyosis (Scott et al., 2013). It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R60P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved, although in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000256128	SCV002208527	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 60 of the ABCA12 protein (p.Arg60Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital ichthyosis (PMID: 22992804, 36980989). ClinVar contains an entry for this variant (Variation ID: 264998). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509340	SCV002819823	uncertain significance	not specified	2022-12-25	criteria provided, single submitter	clinical testing	Variant summary: ABCA12 c.179G>C (p.Arg60Pro) results in a non-conservative amino acid change in 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 250790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.179G>C has been reported in the literature in at least one compound heterozygous individual affected with Harlequin Ichthyosis (Scott_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.