1-94005499-C-T

Position:

• chr1-94005499-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The ENST00000370225.4(ABCA4):​c.6089G>A​(p.Arg2030Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000477 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: ABCA4 ENST00000370225.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 6.06

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000370225.4
• PP5: Variant 1-94005499-C-T is Pathogenic according to our data. Variant chr1-94005499-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94005499-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94005499-C-T is described in Lovd as [Pathogenic]. Variant chr1-94005499-C-T is described in Lovd as [Pathogenic]. Variant chr1-94005499-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.6089G>A	p.Arg2030Gln	missense_variant	44/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.5867G>A	p.Arg1956Gln	missense_variant	43/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.6089G>A	p.Arg2030Gln	missense_variant	44/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000465352.1	n.505G>A		non_coding_transcript_exon_variant	5/6	5
ABCA4	ENST00000484388.1	n.203G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000354 AC: 89 AN: 251390 Hom.: 0 AF XY: 0.000361 AC XY: 49 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000479 AC: 700 AN: 1461864 Hom.: 0 Cov.: 30 AF XY: 0.000476 AC XY: 346 AN XY: 727234

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000572

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74458

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	ABCA4: PS1, PM2, PM3, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2030 of the ABCA4 protein (p.Arg2030Gln). This variant is present in population databases (rs61750641, gnomAD 0.06%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 22229821, 23143460). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99428). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	Published functional studies demonstrate a mild damaging effect (PMID: 32845050); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27491360, 11527935, 18854780, 28559085, 30798147, 32531858, 34647987, 29925512, 25283059, 9973280, 11379881, 27596865, 27820952, 28044389, 28118664, 24713488, 24265693, 26103963, 29555955, 23891399, 30718709, 30215852, 31456290, 31589614, 32619608, 34327195, 34426522, 32815999, 33851411, 32467599, 35119454, 32845050) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2017	The ABCA4 c.6089G>A;p.Arg2030Gln variant has been published in several individuals with Stargardt disease and other ABVA4-related disorders (Bertelsen 2014, Cideciyan 2005, Duncker 2015, Jaakson 2003, Lewis 1999, Webster 2001, Zhang 2015). However, the variant has also been published on the same allele as another pathogenic variant, p.Met1Val (Eisenberger 2013, Maia-Lopes 2009). The variant is listed in the ClinVar database (Variation ID: 99428) and the dbSNP variant database (rs61750641) with an allele frequency of 0.0615 percent (8/12998 alleles) in the Exome Variant Server and 0.03609 percent (100/277108 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved across species, occurs in a transporter domain, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. This variant would be causative for autosomal recessive Stargardt disease and other ABCA4-related disorders (OMIM#601691). References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Cideciyan AV et al. ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4739-46. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Eisenberger T et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013 Nov 12;8(11):e78496. Jaakson K et al Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat. 2003 Nov;22(5):395-403. Lewis RA et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999 Feb;64(2):422-34. Maia-Lopes S et al. ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis. Mol Vis. 2009;15:584-91. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. Zhang Q et al. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci Rep. 2016 Sep 6;6:32792. -

Severe early-childhood-onset retinal dystrophy Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 25, 2023	- -
Pathogenic, 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 pathogenic. The 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), 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 (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (72 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 2 domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than 30 patients with Stargardt disease or ABCA4-related eye disease in the literature where a 2nd disease-causing variant was identified in trans (PMIDs: 30718709; 30670881; 29925512; 28044389; 23953153; 23499370; 18854780; 11379881). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -

Retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 08, 2019	- -

Progressive cone dystrophy (without rod involvement) Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Age related macular degeneration 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 23, 2018

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3,PP5. -

ABCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

The ABCA4 c.6089G>A variant is predicted to result in the amino acid substitution p.Arg2030Gln. This variant has been reported many times as causative for retinal disorders (see for example Lewis et al. 1999. PubMed ID: 9973280; Duncker et al. 2015. PubMed ID: 25283059). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94471055-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99428/). This variant is interpreted as pathogenic. -

Macular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Vitreoretinopathy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0080	.;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	.;D
Vest4		0.93
MVP		0.98
MPC		0.50
ClinPred		0.18	T
GERP RS		5.0
Varity_R		0.56
gMVP		0.92

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: rs61750641; hg19: chr1-94471055;