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

dbSNP: rs368846708

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408538	SCV000281853	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000323631	SCV000359428	uncertain significance	Retinitis Pigmentosa, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV000278622	SCV000359430	uncertain significance	Cone-Rod Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000338922	SCV000359431	uncertain significance	Macular degeneration	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000425865	SCV000520829	uncertain significance	not provided	2020-09-16	criteria provided, single submitter	clinical testing	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: 23096905, 26593885, 28118664, 27813578, 29178665, 31618812)
Illumina Laboratory Services, Illumina	RCV000778260	SCV000914432	uncertain significance	ABCA4-related disorder	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.
Invitae	RCV000425865	SCV003523423	pathogenic	not provided	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 959 of the ABCA4 protein (p.Thr959Ala). This variant is present in population databases (rs368846708, gnomAD 0.007%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 23096905; Invitae). ClinVar contains an entry for this variant (Variation ID: 236095). 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. This variant disrupts the p.Thr959 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10958763, 24097981; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.