ClinVar Genomic variation as it relates to human health

The R2106H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2106H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2106H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this residue (R2106C, R2106P) and in nearby residues (R2107C, R2107P, R2107H) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg2106 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11379881, 23143460, 25283059, 28355279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 377409). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 28327576, 28947085). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2106 of the ABCA4 protein (p.Arg2106His).

Variant summary: ABCA4 c.6317G>A (p.Arg2106His) 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. A different variant located at the same codon, c.6316C>T (p.Arg2106Cys) has been classified as Pathogenic supporting the critical relevance of the Arg 2016 codon to ABCA4 protein function. The variant allele was found at a frequency of 4e-06 in 251278 control chromosomes. c.6317G>A has been reported in the literature as a presumably biallelic compound heterozygous genotype in multiple individuals from diverse ethncities affected with features of ABCA4-associated sectrum of disease such as rapid onset Choriotetinopathy, Stargardt Disease, Cone-Rod Dystrophy and Retinitis Pigmentosa (example, Lee_2017, Tanaka_2018, Tian_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28327576, 28947085, 35657619). ClinVar contains an entry for this variant (Variation ID: 377409). Based on the evidence outlined above, the variant was classified as likely pathogenic.