Submissions for variant NM_000350.3(ABCA4):c.6088C>T (p.Arg2030Ter)

gnomAD frequency: 0.00001  dbSNP: rs61751383

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085786	SCV000490381	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25544989, 26551331, 9973280, 28947085, 29186038, 25525159, 33090715, 35119454, 32619608, 29641573, 23755871, 22589445, 34758253, 30093795, 26780318, 33691693, 33301772, 26247787, 29925512)
Fulgent Genetics, Fulgent Genetics	RCV000763437	SCV000894204	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2022-03-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000505162	SCV001135326	pathogenic	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085786	SCV001222421	pathogenic	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2030*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61751383, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ABCA4-related retinal diseases (PMID: 25544989, 28947085). ClinVar contains an entry for this variant (Variation ID: 7907). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000504794	SCV001241286	pathogenic	Retinal dystrophy	2019-03-07	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000505162	SCV001548077	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542555	SCV001760043	likely pathogenic	Retinitis pigmentosa 19		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000787773	SCV001983385	pathogenic	Stargardt disease	2021-10-25	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002512903	SCV003761278	pathogenic	ABCA4-related retinopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg2030Ter variant in ABCA4 was identified by our study, in the compound heterozygous state along with a pathogenic variant (ClinVar Variation ID: 7898), in one individual with retinal dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 7898); however, the phase of these variants is unknown at this time. The p.Arg2030Ter variant in ABCA4 has been previously reported in at least six unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989) and segregated with disease in 6 affected relatives from 2 families (PMID: 16546111, PMID: 25544989), but has been identified in 0.01% (4/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61751383). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the six unrelated affected individuals previously reported (PMID: 25312043, PMID: 30718709, PMID: 16546111, PMID: 28947085, PMID: 25544989), two were homozygotes (PMID: 30718709, PMID: 16546111), two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 25544989, ClinVar Variation ID: 99114; PMID: 28947085, ClinVar Variation ID: 236128), and two were compound heterozygotes who carried pathogenic variants with unknown phase (PMID: 25312043, ClinVar Variation ID: 99108, 30218), which increases the likelihood that the p.Arg2030Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7907) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 2030, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1_Strong (Richards 2015).
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000787773	SCV004030355	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Neuberg Centre For Genomic Medicine, NCGM	RCV003447472	SCV004175776	pathogenic	Leber congenital amaurosis 14	2023-02-14	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV000504794	SCV004706448	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000504794	SCV005073167	pathogenic	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000505162	SCV005400977	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-06-22	criteria provided, single submitter	clinical testing	The stop gained variant c.6088C>T(p.Arg2030Ter) in ABCA4 gene has been observed in homozygous or compound heterozygous state in multiple individual(s) with ABCA4-related retinal diseases (Tanaka et. al., 2018; González-del Pozo et. al., 2014, Singh HP, et al., 2006). The (p.Arg2030Ter) variant is reported with 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The nucleotide change c.6088C>T in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in ABCA4 are known to be pathogenic (Jiang et. al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000008365	SCV000028573	pathogenic	Retinal dystrophy, early-onset severe	2006-05-01	no assertion criteria provided	literature only
Retina International	RCV000085786	SCV000117928	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505162	SCV000599006	pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504794	SCV000599007	pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787773	SCV000926778	pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000085786	SCV001923531	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085786	SCV001954312	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528093	SCV004104692	pathogenic	ABCA4-related disorder	2024-08-29	no assertion criteria provided	clinical testing	The ABCA4 c.6088C>T variant is predicted to result in premature protein termination (p.Arg2030*). This variant has been reported many times in individuals with Stargardt disease (see for examples Lewis et al. 1999. PubMed ID: 9973280; Pozo et al. 2014. PubMed ID: 25544989; Table S4 in Jiang et al. 2016. PubMed ID: 26780318; Table S2 in Del Pozo-Valero et al. 2022. PubMed ID: 35119454). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ABCA4 are expected to be pathogenic. Given the evidence, we interpret c.6088C>T (p.Arg2030*) as pathogenic.