Submissions for variant NM_000350.3(ABCA4):c.1804C>T (p.Arg602Trp)

gnomAD frequency: 0.00002  dbSNP: rs61749409

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408597	SCV000281831	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085428	SCV000321339	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect suggestive of protein misfolding (Wiszniewski et al., 2005); 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: 24444108, 31429209, 33706644, 28118664, 28041643, 28181551, 28947085, 28446513, 29186038, 23755871, 29641573, 29114839, 30093795, 28559085, 28838317, 32036094, 32581362, 32845050, 31216405, 34327195, 33781268, 31589614, 32619608, 33090715, 33301772, 33261146, 35657619, 35119454, 20696155, 25472526, 36338671, 22449572, 23982839, 34906470, 25910913, 9973280, 16103129, 23695285)
Eurofins Ntd Llc (ga)	RCV000085428	SCV000701678	pathogenic	not provided	2016-10-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000850520	SCV000992724	pathogenic	Cone-rod dystrophy 3; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2018-10-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085428	SCV001223382	pathogenic	not provided	2025-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 602 of the ABCA4 protein (p.Arg602Trp). This variant is present in population databases (rs61749409, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease and autosomal recessive retinitis pigmentosa (PMID: 16103129, 23755871). ClinVar contains an entry for this variant (Variation ID: 99084). 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: 16103129). This variant disrupts the p.Arg602 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20696155, 22449572, 23982839, 25472526, 25910913). 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.
Blueprint Genetics	RCV000504951	SCV001240003	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085428	SCV001447936	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV001353025	SCV001548136	likely pathogenic	Cone-rod dystrophy 3	2021-01-30	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000408597	SCV001573247	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.1804C>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: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723664	SCV001950194	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg602Trp variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity	RCV000085428	SCV002019722	pathogenic	not provided	2019-10-15	criteria provided, single submitter	clinical testing
DASA	RCV001849310	SCV002107086	pathogenic	ABCA4-related disorder	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16103129) - PS3.The c.1804C>T;p.(Arg602Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 99084; PMID: 28181551; 28118664; 28041643; 24444108; 23982839; 23755871; 9973280) - PS4. The variant is present at low allele frequencies population databases (rs61749409 – gnomAD 0.0004385%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg602Trp) was detected in trans with a pathogenic variant (PMID: 28181551; PMID: 16103129; PMID: 24444108; PMID: 23982839; PMID: 23755871) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16103129) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000408597	SCV002503795	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with tryptophan at codon 602 of the ABCA4 protein, p.(Arg602Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is present in the extracellular domain. There is a moderate physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort 0.004%, which is consistent with recessive disease (rs61749409, 11/250,870 alleles, 0 homozygotes in gnomAD v2.1). It has been reported compound heterozygous with another pathogenic allele and homozygous most commonly in Stargardt disease cases, and also cases of cone-rod dystrophy and retinitis pigmentosa co-segregating with disease (PMID: 9973280, 16103129, 23695285). In vitro functional assays demonstrate that the missense substitution prevents correct localisation of the protein in to the rod outer segment, and perturbs ATPase activity (PMID: 16103129). Additionally, 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, PS3_Supporting, PP1, PP3.
3billion, Medical Genetics	RCV002250560	SCV002521184	pathogenic	Retinitis pigmentosa 19	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099084). The variant has been reported to be in trans with other pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16103129). A different missense change at the same codon (p.Arg602Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099085). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002498452	SCV002809677	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-03-06	criteria provided, single submitter	clinical testing
Pangenia Genomics, Pangenia Inc.	RCV002250560	SCV003925675	pathogenic	Retinitis pigmentosa 19	2021-11-18	criteria provided, single submitter	research	The ABCA4, c.1804C>T (p.Arg602Trp) variant is at extremely low frequency in population database. In vitro functional studies demonstrated that this variant results in protein mis-folding and mis-localization [PMID: 16103129]. This variant has been observed in many individuals with autosomal recessive retinopathy, in homozygosity, or with another variant in ABCA4 gene, including null variants and missense variants [PMID: 16103129, 30093795, 9973280, 23755871, 32619608, 29186038]. This variant has been found to co-segregate with retinitis pigmentosa, Stargardt disease 1 or Cone-rod dystrophy in multiple families (PMID: 16103129, 23755871, 32619608, 29114839). Multiple lines of computational evidence support a deleterious effect on the gene/gene product (REVEL = 0.934). This variant has multiple submissions in ClinVar (Variation ID: 99084).
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324506	SCV004030271	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000504951	SCV005072189	pathogenic	Retinal dystrophy	2011-01-01	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002498452	SCV005415992	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP1+PP3_Strong
Retina International	RCV000085428	SCV000117565	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504951	SCV000598942	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004558305	SCV005046937	pathogenic	Stargardt disease 3		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV001849310	SCV005367178	pathogenic	ABCA4-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The ABCA4 c.1804C>T variant is predicted to result in the amino acid substitution p.Arg602Trp. This variant has been reported in multiple individuals with ABCA4-related retinal disease (Lewis et al. 1999. PubMed ID: 9973280; Riveiro-Alvarez et al. 2013. PubMed ID: 23755871; Xin et al. 2015. PubMed ID: 26161775). Of note, this variant has been reported to cause mislocalized protein and results in an early disease onset and severe disease phenotype (Wiszniewski et al. 2005. PubMed ID: 16103129). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.