ClinVar Miner

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

gnomAD frequency: 0.00132  dbSNP: rs1762111
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Total submissions: 18
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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 likely pathogenic not provided 2021-12-21 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, 32581362, 25087612, 23953153, 23143460, 17982420, 15696369, 23982839, 33836713, 11726554, 11527935, 30718709, 29925512, 28118664, 28771251, 28041643, 29555955, 27535533, 28838317, 29068140, 29975949)
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 2021-12-06 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. 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
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
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787502 SCV000926468 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000505175 SCV000926785 likely pathogenic Retinal dystrophy 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, 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

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