ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2875A>G (p.Thr959Ala) (rs368846708)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425865 SCV000520829 uncertain significance not provided 2016-12-23 criteria provided, single submitter clinical testing The T959A variant in the ABCA4 gene has been previously reported in two unrelated patients with Stargardt disease who were heterozygous for the T959A variant and heterozygous for another ABCA4 variant, however, familial segregation information was not included (Oldani et al., 2012; Sciezynska et al., 2015). The T959A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T959A 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variants in the same residue, T959I, was previously reported in the compound heterozygous state with a second ABCA4 variant in a patient with Stargardt disease (Rivera et al., 2000). We interpret T959A as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000323631 SCV000359428 uncertain significance Retinitis Pigmentosa, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000373695 SCV000359429 uncertain significance Stargardt Disease, Recessive 2016-06-14 criteria provided, single submitter clinical testing The c.2875A>G (p.Thr959Ala) variant has been reported in one study in which it is found in a compound heterozygous state with a second missense variant in one individual with Stargardt disease (Oldani et al. 2012). Control data are unavailable for the p.Thr959Ala variant which is reported at a frequency of 0.00003 in the European (Non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles only in a region of good coverage hence the variant is presumed to be rare. Oldani et al. (2012) note that the variant, which lies in the cytoplasmic domain of the protein, results in the substitution of a polar amino acid for a non-polar one and that the Thr959 residue is conserved at this position in vertebrates. The evidence for this variant is limited. The p.Thr959Ala variant is therefore classified as a variant of unknown significance, but suspicious for pathogenicity for Stargardt disease.
Illumina Clinical Services Laboratory,Illumina RCV000278622 SCV000359430 uncertain significance Cone-Rod Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000338922 SCV000359431 uncertain significance Macular degeneration 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778260 SCV000914432 uncertain significance ABCA4-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The ABCA4 c.2875A>G (p.Thr959Ala) missense has been reported in one study in which it was found in a compound heterozygous state with a second missense variant in one individual with Stargardt disease (Oldani et al. 2012). Control data are unavailable for the p.Thr959Ala variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles only in a region of good coverage; hence, the variant is presumed to be rare. Oldani et al. (2012) note that the variant, which lies in the cytoplasmic domain of the protein, results in the substitution of a polar amino acid for a non-polar one and that the Thr959 residue is conserved at this position in vertebrates. The evidence for this variant is limited. The p.Thr959Ala variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for ABCA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408538 SCV000281853 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing

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