Submissions for variant NM_000350.3(ABCA4):c.5693G>A (p.Arg1898His)

gnomAD frequency: 0.00153  dbSNP: rs1800552

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408593	SCV000281934	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085752	SCV000608476	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ABCA4: PM2, PM3, BP4, BP5
Ambry Genetics	RCV000623966	SCV000742854	uncertain significance	Inborn genetic diseases	2014-10-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000085752	SCV000855135	uncertain significance	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778998	SCV000915439	pathogenic	ABCA4-Related Disorders	2018-09-18	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000085752	SCV001047969	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075015	SCV001240625	uncertain significance	Retinal dystrophy	2018-02-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196150	SCV001366671	uncertain significance	Age related macular degeneration 2	2019-04-09	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP5.
GeneDx	RCV000085752	SCV001772092	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	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 (Sun et al., 2000; Garces et al., 2020); In silico analysis supports 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, 28118664, 28559085, 9973280, 11017087, 9295268)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470766	SCV002768545	likely benign	Cone-rod dystrophy 3	2021-05-06	criteria provided, single submitter	clinical testing	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
Institute of Human Genetics, University of Leipzig Medical Center	RCV000408593	SCV003804644	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-01-31	criteria provided, single submitter	clinical testing	_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
Institute of Human Genetics, University of Leipzig Medical Center	RCV002470766	SCV003921026	pathogenic	Cone-rod dystrophy 3	2023-03-28	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM3_VSTR, PM5
Retina International	RCV000085752	SCV000117893	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787513	SCV000926480	likely pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787764	SCV000926769	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000085752	SCV001553374	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Clinical Genetics, Academic Medical Center	RCV000085752	SCV001921177	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085752	SCV001953417	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085752	SCV001976099	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000085752	SCV001978734	uncertain significance	not provided		no assertion criteria provided	clinical testing