ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP5.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), cone-rod dystrophy 3 (MIM #6041163), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (438 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (128 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the second transmembrane domain (TMD2; PMID: 33375396). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, an alternative change of stronger Grantham score (p.Arg1898Cys) has been reported as a VUS (ClinVar) and observed in several individuals with (PMID: 26743751, 25474345). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported in patients with Stargardt disease and retinitis pigmentosa (PMID: 30718709; 10958763), however it has been classified as pathogenic, likely pathogenic, a VUS and likely benign (ClinVar). (I) 1004 - This variant has moderate functional evidence supporting normal protein function, with in vitro studies demonstrating a minimal effect on basal ATPase activity and robust N-Ret-PE-stimulated ATPase activity (PMID: 11017087; 33375396). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

_x000D_This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.2588G>C and NM_000350.3:c.1411G>A. Criteria applied: PM3_VSTR, PM5_STR

Published functional studies demonstrate that the R1898H variant results in ATPase activity that is indistinguishable from wild type and has minimal effect on the structure and function of the protein (PMID: 11017087, 33375396); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 32483926, 22229821, 20029649, 21293320, 9054934, 23953153, 15579991, 10958763, 31884623, 33375396, 22449572, 34426522, 33851411, 30718709, 31456290, 29207047, 29555955, 29925512, 28559085, 9295268, 28118664, 9973280, 11017087, 33749171, 35120629, 36460718, 32307445)

Criteria applied: PM3_VSTR,PM5

ABCA4: PM2, PM3, BP4, BP5

The ABCA4 c.5693G>A (p.Arg1898His) missense variant has been reported in at least eight studies in which it was found in 18 individuals with Stargardt disease, including six compound heterozygotes, two heterozygotes, four who carried the variant in a complex allele, and six in whom zygosity information is not provided, and in a compound heterozygous state in one proband with cone-rod dystrophy (Allikmets et al. 1997a; Lewis et al. 1999; Rivera et al. 2000; Ernest et al. 2009; Anastasakis et al. 2011; Duno et al. 2012; Westeneng-van Haaften et al. 2012; Fujinami et al. 2013). The p.Arg1898His variant was identified in a heterozygous state in one of 880 control chromosomes (Allikmets et al. 1997a; Lewis et al. 1999; Rivera et al. 2000) and is reported at a frequency of 0.00281 in the European (non-Finnish) population of the Exome Aggregation Consortium. Westeneng-van Haaften et al. (2012) predicted a decreased protein yield in the presence of the variant and suggested the variant may have a mild effect; however, two other studies did not observe a difference compared to wild type (Allikmets et al. 1997b; Sun et al. 2000). Based on the collective evidence, the p.Arg1898His variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The ABCA4 p.R1898H variant was identified in the literature as a heterozygous, compound heterozygous, or complex variant in >20 individuals with age-related macular degeneration, Stargardt Disease, atypical maculopathy or bilateral severe familial exudative vitreoretinopath (Allikmets_1997_PMID:9295268; Rivera_2000_PMID:10958763; Anastasakis _2011_PMID:21293320; Duno_2012_PMID:22229821; Fujinami_2013_PMID:23953153; Lin_2018_PMID:29207047; Westeneng-van Haaften_2012_PMID:22449572). However, this variant has been reported in an individual with Stargardt-flavimaculatus who also carried two likely pathogenic variants in the ABCA4 gene (Duno_2012_PMID:22229821). The variant was identified in dbSNP (ID: rs1800552) and in ClinVar (classified as uncertain significance by Ambry Genetics, EGL Genetics and three other laboratories; as likely benign by Invitae; as likely pathogenic by Institute of Human Genetics, Univ. Regensburg and Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet; and as pathogenic by Illumina). The variant was identified in control databases in 438 of 282700 chromosomes at a frequency of 0.001549, and was observed at the highest frequency in the European (non-Finnish) population in 324 of 129094 chromosomes (freq: 0.002510) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R1898 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. Functional ATPase assays have demonstrated that the p.R1898H variant displays ATPase activity comparable to wild type (Sun_2000_PMID:11017087). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The ABCA4 c.5693G>A variant is predicted to result in the amino acid substitution p.Arg1898His. This variant has been reported many times, often in the compound heterozygous state, in individuals with clinically diagnosed Stargardt disease (see for examples Rivera et al. 2000. PubMed ID: 10958763; Scholl et al. 2002. PubMed ID: 11923272). This variant has also been reported in patients with late-onset Stargardt disease and age-related macular degeneration (Fujinami et al. 2013. PubMed ID: 23953153; Rivera et al. 2000. PubMed ID: 10958763). However, this variant is reported in 0.25% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including multiple homozygous individuals in the latest dataset (https://gnomad.broadinstitute.org/variant/1-94010821-C-T?dataset=gnomad_r4), which is more frequent than expected for a pathogenic variant. This variant has more recently been reported in individuals with Stargardt disease who harbor two other ABCA4 variants which have been reported as more likely to be causative (Fujinami et al. 2019. PubMed ID: 29925512). An in vitro functional study determined that this amino acid substitution did not significantly affect the biochemical function of the ABCA4 protein compared to wildtype (Sun et al. 2000. PubMed ID: 11017087). This variant has conflicting classifications, from likely pathogenic to likely benign, in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99398/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the conflicting evidence.