ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4610C>T (p.Thr1537Met)

gnomAD frequency: 0.00006  dbSNP: rs62642575
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085659 SCV000779602 uncertain significance not provided 2022-06-11 criteria provided, single submitter clinical testing Identified without a second ABCA4 variant in individuals with retinal dystrophy (Rivera et al., 2000; Weisschuh et al., 2020; Sun et al., 2021; Ng et al., 2022); Identified in the heterozygous state in patients with nonsyndromic orofacial clefting (Peng et al., 2016); Published functional studies suggest a damaging effect with approximately 60% lower ATPase activity and 60% lower phospholipid transport activity compared to wild type (Quazi et al., 2013); 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: 24097981, 34426522, 27527345, 31630094, 32531858, 33846575, 33301772, 10958763, 28118664)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002608 SCV001160585 uncertain significance not specified 2019-06-05 criteria provided, single submitter clinical testing The ABCA4 c.4610C>T, p.Thr1537Met variant (rs62642575) is reported in the medical literature in two individuals with Stargardt disease, but information on an additional pathogenic variant in these individuals was not provided (Rivera 2000, Schulz 2017). The variant is reported in the ClinVar database (Variation ID: 99306) and in the general population with an allele frequency of 0.01% (34/282866 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Cell culture experiments show this variant slightly reduces function of the protein. However, due to limited information, the clinical significance of the variant is uncertain at this time. References: Quazi F et al. Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. J Biol Chem. 2013 Nov 29;288(48):34414-26. Rivera A et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Oct;67(4):800-13 Schulz HL et al. Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):394-403.
Labcorp Genetics (formerly Invitae), Labcorp RCV000085659 SCV001233683 pathogenic not provided 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1537 of the ABCA4 protein (p.Thr1537Met). This variant is present in population databases (rs62642575, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of Stargardt disease (PMID: 28118664, 31630094, 33301772; Invitae). ClinVar contains an entry for this variant (Variation ID: 99306). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 24097981). For these reasons, this variant has been classified as Pathogenic.
3billion RCV000408504 SCV002521013 likely pathogenic Severe early-childhood-onset retinal dystrophy 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:24097981). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ABCA4 related disorder (ClinVar ID: VCV000099306 / PMID: 10958763). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Retina International RCV000085659 SCV000117799 not provided not provided no assertion provided not provided

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