rs1800552

Positions:

• chr1-94010821-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5 BP4_Strong BS2_Supporting

The NM_000350.3(ABCA4):​c.5693G>A​(p.Arg1898His) variant causes a missense change. The variant allele was found at a frequency of 0.00176 in 1,614,100 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1898C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:12 B:2 O:1
• Conservation: PhyloP100: 4.25

Genes affected

ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94010822-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0100162625).
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.5693G>A	p.Arg1898His	missense_variant	40/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.5471G>A	p.Arg1824His	missense_variant	39/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.5693G>A	p.Arg1898His	missense_variant	40/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000465352.1	n.109G>A		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00156 AC: 391 AN: 251332 Hom.: 0 AF XY: 0.00152 AC XY: 206 AN XY: 135854

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00179 AC: 2623 AN: 1461862 Hom.: 3 Cov.: 31 AF XY: 0.00177 AC XY: 1289 AN XY: 727230

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74436

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00179 AC: 217

EpiCase AF: 0.00191

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:12 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8 Benign:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2024	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ABCA4: PM2, PM3, BP4, BP5 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

ABCA4-related disorder Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 15, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 18, 2018	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. -

Cone-rod dystrophy 3 Pathogenic:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 28, 2023	Criteria applied: PM3_VSTR,PM5 -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 31, 2023

_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 -

Stargardt disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Age related macular degeneration 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 09, 2019

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2014

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-1.8	.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	3.9	.;N
REVEL	Uncertain	0.43
Sift	Benign	0.57	.;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	.;B
Vest4		0.68
MVP		0.82
MPC		0.10
ClinPred		0.019	T
GERP RS		3.6
Varity_R		0.047
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800552; hg19: chr1-94476377; COSMIC: COSV105292032; COSMIC: COSV105292032;