Submissions for variant NM_000350.3(ABCA4):c.4685T>C (p.Ile1562Thr)

gnomAD frequency: 0.00132  dbSNP: rs1762111

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408556	SCV000281902	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085664	SCV000321352	pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant reduces ATP-binding ability (Shroyer et al., 2001); 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, 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)
Illumina Laboratory Services, Illumina	RCV000335992	SCV000359308	uncertain significance	Cone-Rod Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000407014	SCV000359309	uncertain significance	Retinitis Pigmentosa, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000314956	SCV000359310	uncertain significance	ABCA4-Related Disorders	2016-06-14	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000085664	SCV000574765	likely pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Broad Institute Rare Disease Group, Broad Institute	RCV001005005	SCV001164566	uncertain significance	Cone-rod dystrophy 3	2018-12-03	criteria provided, single submitter	research	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).
Invitae	RCV000085664	SCV001202642	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV000505175	SCV001239626	pathogenic	Retinal dystrophy	2018-11-23	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002509209	SCV002818576	likely pathogenic	Severe early-childhood-onset retinal dystrophy; Stargardt disease	2023-01-11	criteria provided, single submitter	clinical testing
Retina International	RCV000085664	SCV000117804	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505175	SCV000598983	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787502	SCV000926468	likely pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000505175	SCV000926785	likely pathogenic	Retinal dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787778	SCV000926786	likely pathogenic	Cone-rod dystrophy	2018-04-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000085664	SCV001550688	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Clinical Genetics, Academic Medical Center	RCV000085664	SCV001919283	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085664	SCV001954453	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085664	SCV001975864	uncertain significance	not provided		no assertion criteria provided	clinical testing