Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000999861 | SCV000883317 | likely pathogenic | not specified | 2018-07-09 | criteria provided, single submitter | clinical testing | The ABCA4 c.2912C>A;p.Thr971Asn variant has been published in individuals with Stargardt disease, including in an individual homozygous for the variant (Battu 2015, Webster 2001). The variant is listed in the ClinVar database (Variation ID: 99173) and the dbSNP variant database (rs61749450) and in the Genome Aggregation Database with an allele frequency of 0.0004065 percent (1/245988 alleles). The amino acid at this position is well conserved across species, and part of a conserved Walker type A binding motif (Galinier 2002). As such, this variant has been shown to cause abolished ATP binding and retinal-stimulated ATP hydrolysis (Sun 2000). Considering available information, this variant is classified as likely pathogenic. References: Battu R et al. Identification of Novel Mutations in ABCA4 Gene: Clinical and Genetic Analysis of Indian Patients with Stargardt Disease. Biomed Res Int. 2015;2015:940864. Galinier A et al. A new family of phosphotransferases with a P-loop motif. J Biol Chem. 2002 Mar 29;277(13):11362-7. Sun H et al. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet. 2000 Oct;26(2):242-6. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. |
| Molecular Genetics, |
RCV002225080 | SCV002503719 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace threonine with asparagine at codon 971 of the ABCA4 protein, p.(Thr971Asn). The threonine residue is highly conserved (100 vertebrates, UCSC), and located in the ATP binding cassette transporter 1 domain. There is a moderate physicochemical difference between threonine and asparagine. The variant is present in a large population cohort at a frequency of 0.0004%, which is consistent with recessive disease (rs61749450, 1/251,228 alleles, 0 homozygotes in gnomAD v2.1). Two noncansanguineous homozygous cases with Stargardt disease have been reported (PMID: 25922843, 28355279). In vitro ATPase assays of the variant show little basal ATPase activity and little or no retinal-stimulated ATPase activity (PMID: 11017087). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM3, PS3_Supporting, PP3. |
| Labcorp Genetics |
RCV000085522 | SCV003523395 | pathogenic | not provided | 2023-08-17 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 971 of the ABCA4 protein (p.Thr971Asn). This variant is present in population databases (rs61749450, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of Stargardt disease (PMID: 25922843, 28355279, 31934596). ClinVar contains an entry for this variant (Variation ID: 99173). 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. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic. |
| Retina International | RCV000085522 | SCV000117659 | not provided | not provided | no assertion provided | not provided |