Submissions for variant NM_000350.3(ABCA4):c.4577C>T (p.Thr1526Met)

gnomAD frequency: 0.00016  dbSNP: rs61750152

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085656	SCV000229390	pathogenic	not provided	2015-02-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000085656	SCV000511899	pathogenic	not provided	2023-01-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced basal ATPase activity and almost absent retinal-stimulated activity (Sun et al., 2000); 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: 30653986, 34240658, 34758253, 32467599, 11527935, 21558428, 23918662, 11702214, 11726554, 23755871, 19265867, 21911583, 14517951, 9973280, 26551331, 23982839, 23143460, 30337596, 29925512, 28559085, 31456290, 32581362, 31618761, 32845068, 33301772, 32037395, 35119454, 35409265, 11017087, 19074458, 25082885)
Ambry Genetics	RCV000623715	SCV000742931	likely pathogenic	Inborn genetic diseases	2017-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085656	SCV001200444	pathogenic	not provided	2025-01-01	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 1526 of the ABCA4 protein (p.Thr1526Met). This variant is present in population databases (rs61750152, gnomAD 0.01%). This missense change has been observed in individuals with Stargardt disease or cone-rod dystrophy and Stargardt disease in at least one family and has been observed in unrelated individuals affected with Stargardt disease or cone-rod dystrophy (PMID: 9973280, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99303). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075849	SCV001241488	pathogenic	Retinal dystrophy	2019-08-02	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000177509	SCV001573618	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.4577C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000177509	SCV002503703	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 methionine at codon 1526 of the ABCA4 protein, p.(Thr1526Met). The threonine residue is moderately conserved (100 vertebrates, UCSC), and in the extracellular domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with recessive disease (rs61750152, 18/282,882 alleles, 0 homozygotes in gnomAD v2.1.1). Multiple Stargardt disease/ABCA4 retinopathy cases are compound heterozygous with a second pathogenic variant or homozygous (PMID: 9973280, 19074458, 28446513), and at least two affected segregations in a single family have been reported for the variant (PMID: 19074458). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP3.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075849	SCV005071193	likely pathogenic	Retinal dystrophy	2019-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025160	SCV005658880	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085656	SCV000117796	not provided	not provided		no assertion provided	not provided
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210286	SCV000259076	likely pathogenic	Retinitis pigmentosa 19	2015-01-23	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000177509	SCV000598981	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002827	SCV001160844	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV001542561	SCV001760051	pathogenic	Age related macular degeneration 2		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000210286	SCV001760052	likely pathogenic	Retinitis pigmentosa 19		no assertion criteria provided	clinical testing
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000177509	SCV005047021	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research