Submissions for variant NM_000392.5(ABCC2):c.2078G>A (p.Gly693Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003837780	SCV004631957	likely pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 693 of the ABCC2 protein (p.Gly693Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Dubin-Johnson syndrome (PMID: 31450232, 32758197). 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 ABCC2 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly693 amino acid residue in ABCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31544333, 32183854). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
PreventionGenetics, part of Exact Sciences	RCV004723508	SCV005336616	likely pathogenic	ABCC2-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The ABCC2 c.2078G>A variant is predicted to result in the amino acid substitution p.Gly693Glu. This variant was reported in the compound heterozygous state in two individuals with autosomal recessive Dubin-Johnson syndrome (Wang et al. 2020. PubMed ID: 31450232; Kim et al. 2020. PubMed ID: 32758197). An alternate nucleotide change affecting the same amino acid (p.Gly693Arg) has also been reported in individuals with Dubin-Johnson syndrome (Corpechot et al. 2019. PubMed ID: 31544333; Wu et al. 2020. PubMed ID: 32183854). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.