rs1762111

Positions:

chr1-94021934-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_000350.3(ABCA4):c.4685T>C(p.Ile1562Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,614,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. I1562V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:12O:1

Conservation

PhyloP100: 5.77

Variant links:

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]

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000350.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0339157).

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 link	c.4685T>C	p.Ile1562Thr	missense_variant	33/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.4463T>C	p.Ile1488Thr	missense_variant	32/49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.4685T>C	p.Ile1562Thr	missense_variant	33/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000460514.1 link	n.179T>C		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

196

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00120

AC:

301

AN:

251412

Hom.:

AF XY:

0.00113

AC XY:

154

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00159

AC:

2327

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1124

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

152296

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00223

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.000990

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00130

AC:

158

EpiCase

AF:

0.00164

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:6Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCA4 p.Ile1562Thr variant was not identified in the Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs1762111), ClinVar (reported as uncertain signficance (5), pathogenic and likely pathogenic), Clinvitae and MutDB. The variant was identified in control databases in 353 of 282818 chromosomes (1 homozygous) at a frequency of 0.001248 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 283 of 129140 chromosomes (freq: 0.002191), Other in 14 of 7228 chromosomes (freq: 0.001937), Ashkenazi Jewish in 17 of 10364 chromosomes (freq: 0.00164), European (Finnish) in 20 of 25124 chromosomes (freq: 0.000796), South Asian in 7 of 30614 chromosomes (freq: 0.000229), Latino in 8 of 35432 chromosomes (freq: 0.000226) and African in 4 of 24964 chromosomes (freq: 0.00016); it was not observed in the East Asian population. The p.I1562T variant was identified in 1/79 compound heterozygous patients with ABCA4-associated diseases, however was suggested to be benign (Fujinami_2013_PMID: 23982839). Downes et al. (2012) identified the variant in a patient with bull's eye maculopathy who also had an affected parent and sibling, however the I1562T variant was not found to cosegregate with disease (Downes_2012_PMID: 23143460). The variant was also identified in 3/335 patients with Stargardt disease and predicted to be pathogenic (Schulz_2017_PMID: 28118664). The p.Ile1562 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1562 of the ABCA4 protein (p.Ile1562Thr). This variant is present in population databases (rs1762111, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Stargardt disease or cone-rod dystrophy, but there is no convincing evidence that it segregates with disease (PMID: 11527935, 22661472, 28041643, 29975949, 30718709). ClinVar contains an entry for this variant (Variation ID: 99311). 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. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11726554). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2023	The p.Ile1562Thr variant in ABCA4 has been reported in at least 5 individuals with Stargardt disease in association with a second pathogneic or likely pathogenic variant. In addition, it has been identified in the heterozygous state without a clear second pathogenic variant in at least 1 individual with Stargardt disease and 2 individuals with macular degeneration (Allikmets 1997 PMID: 9295268; Testa 2012 PMID: 22661472; Fujinami 2013 PMID: 23953153, Downes 2012 PMID: 23143460. Sung 2019 PMID: 29975949, Lee 2022 PMID: 34874912). The observation of this variant in trans with a loss of function variant in individuals with a mild form of Stargardt disease suggests this variant might act as a hypomorph (Lee 2022 PMID: 34874912). This variant has been identified in 0.288% (10/3472) of Ashkenazi Jewish and in 0.22% (152/68026) of European chromosomes by gnomAD ( v3.1.2 (http://gnomad.broadinstitute.org), and in one homozygous individual in gnomAD (v2.1.1). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant may impact protein function by lowering the ATP-binding affinity of the protein (Shroyer 2001 PMID: 11726554); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PM3_Strong -
Uncertain significance, 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	Aug 30, 2024	Published functional studies demonstrate that the variant reduces ATP-binding ability (PMID: 11726554); 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: 10958763, 11818392, 20849526, 9295268, 11379881, 35120629, 36460718, 31429209, 32581362, 25087612, 23953153, 23143460, 17982420, 15696369, 23982839, 33836713, 30718709, 29925512, 28118664, 28771251, 28041643, 29555955, 28838317, 29068140, 29975949, 34426522, 32531858, 34874912, 34945039, Lee[abstract]2021, 30834176, 11726554, 11527935) -
not provided, no classification provided	literature only	Retina International	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ABCA4: PM3:Strong, PM2:Supporting, PS3:Supporting -

Retinal dystrophy

Pathogenic:4Uncertain:1

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 23, 2018	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

ABCA4-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 25, 2024	The ABCA4 c.4685T>C variant is predicted to result in the amino acid substitution p.Ile1562Thr. This variant has been reported in multiple individuals with ABCA4-related retinal disease (Allikmets et al. 1997. PubMed ID: 9295268; Downes et al. 2012. PubMed ID: 23143460). It has been proposed to be a mild variant (Table S2, Cornelis et al. 2022. PubMed ID: 35120629). This variant is reported in 0.22% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.4685T>C (p.Ile1562Thr) variant has been described in three studies in which it is found in a compound heterozygous state in two individuals with Stargardt disease, a heterozygous state (with no additional variant identified) in a third individual with Stargardt disease, and in a heterozygous state in two individuals with macular degeneration (Allikmets et al. 1997; Testa et al. 2012; Fujinami et al. 2013). The variant was observed in six out of 1260 control alleles (Allikmets et al. 1997; Rivera et al. 2000; Testa et al. 2012) and is reported at a frequency of 0.00218 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies by Shroyer et al. (2001) demonstrated that the p.Ile1562Thr variant results in a substantial reduction in the ATP-binding ability of the protein whilst expression levels are unaffected compared to wild-type. Based on the evidence, the p.Ile1562Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. -

Stargardt disease;C1855465:Severe early-childhood-onset retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jan 11, 2023

- -

Cone-rod dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Stargardt disease

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Retinitis Pigmentosa, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cone-Rod Dystrophy, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cone-rod dystrophy 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The heterozygous p.Ile1562Thr variant in ABCA4 was identified by our study in the compound heterozygous state, with another VUS, in one individual with cone rod dystrophy. This variant has been identified in 0.1266% (351/277160) of chromosomes and 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1762111). Although this variant has been seen in the general population in the homozygous state, its frequency is low enough to be consistent with a recessive carrier frequency with a later age of onset. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies provide some evidence that the p.Ile1562Thr variant may impact protein function by lowering the ATP-binding affinity of the protein (PMID: 11726554). However, these types of assays may not accurately represent biological function. The p.Ile1562Thr variant in ABCA4 has been reported in one individual with cone rod dystrophy, but did not segregate with disease in an affected parent and sibling from the same family (PMID: 11726554). In summary, the clinical significance of the p.Ile1562Thr variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3, BS4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;D

Eigen

Benign

0.040

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.034

T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.6

.;L

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

.;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0050

.;D

Sift4G

Uncertain

0.036

D;D

Polyphen

0.060

.;B

Vest4

0.73

MVP

0.94

MPC

0.11

ClinPred

0.036

GERP RS

5.0

Varity_R

0.29

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over