Submissions for variant NM_000350.3(ABCA4):c.2041C>T (p.Arg681Ter)

dbSNP: rs61749423

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408512	SCV000281841	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085458	SCV000490370	pathogenic	not provided	2022-04-25	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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25544989, 28041643, 28118664, 26872967, 24342785, 24713488, 14517951, 10090887, 29555955, 29925512, 29736279, 28559085, 19074458)
Blueprint Genetics	RCV001073628	SCV001239179	pathogenic	Retinal dystrophy	2019-07-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085458	SCV001245781	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001195987	SCV001366414	pathogenic	Age related macular degeneration 2	2019-08-21	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085458	SCV001393043	pathogenic	not provided	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg681*) 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 (rs61749423, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with retinal disease (PMID: 10090887, 25544989, 28041643, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99114). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Molecular Genetics, University of Zurich	RCV000408512	SCV001548009	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085458	SCV001761996	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085458	SCV003812951	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073628	SCV005073414	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025147	SCV005661350	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-03-27	criteria provided, single submitter	clinical testing
Retina International	RCV000085458	SCV000117595	not provided	not provided		no assertion provided	not provided
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210310	SCV000259074	likely pathogenic	Benign concentric annular macular dystrophy	2015-01-19	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504983	SCV000598948	pathogenic	Leber congenital amaurosis	2015-01-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000085458	SCV001922875	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085458	SCV001954765	pathogenic	not provided		no assertion criteria provided	clinical testing
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004558307	SCV005046941	pathogenic	Stargardt disease 3		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732663	SCV005360403	pathogenic	ABCA4-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The ABCA4 c.2041C>T variant is predicted to result in premature protein termination (p.Arg681*). This variant has been reported in multiple individuals with ABCA4-associated disease (see for example, Maugeri et al. 1999. PubMed ID: 10090887; Chouchene et al. 2013. PubMed ID: 24342785; Table S2, Del Pozo-Valero et al. 2020. PubMed ID: 32619608; Briggs et al. 2001. PubMed ID: 11527935; Supplementary tables, Holtan et al. 2020. PubMed ID: 31429209; Table S1, Schlottmann et al. 2023. PubMed ID: 37217489; Table S2, Carss et al. 2016. PubMed ID: 28041643). Nonsense variants in ABCA4 are expected to be pathogenic. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.