ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4610C>T (p.Thr1537Met) (rs62642575)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408504 SCV000281898 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085659 SCV000779602 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing The T1537M variant in the ABCA4 gene has been reported previously in individuals with Stargardt disease, however, a second disease-causing allele was not identified in one individual (Rivera et al., 2000; Schulz et al., 2017). The T1537M variant is observed in 32/277,204 (0.0115%) global alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The T1537M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro functional studies suggest a damaging effect with approximately 50% lower ATPase activity and 60% lower phospholipid transport activity compared to wild type (Quazi et al., 2013). We interpret T1537M as a variant of uncertain significance.
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.
Invitae RCV000085659 SCV001233683 uncertain significance not provided 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1537 of the ABCA4 protein (p.Thr1537Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs62642575, ExAC 0.1%). This variant has been observed in individual(s) with clinical features of Stargardt disease (PMID: 28118664). ClinVar contains an entry for this variant (Variation ID: 99306). This variant has been reported to affect ABCA4 protein function (PMID: 24097981). 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.
Retina International RCV000085659 SCV000117799 not provided not provided no assertion provided not provided

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