Submissions for variant NM_000350.3(ABCA4):c.768G>T (p.Val256=)

gnomAD frequency: 0.00006  dbSNP: rs62645944

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408540	SCV000281810	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085866	SCV000329045	pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically, the c.768 G>T variant results in low or absent mRNA expression (Maugeri et al., 1999); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26261413, 15161829, 23695285, 28118664, 31429209, 32531858, 31522899, 33706644, 22968130, 19074458, 24453473, 22264887, 10090887, 23891399, 28771251, 29310964, 31618761, 30903310, 32581362, 32810830, 33851411, 31573552, 31589614, 29555955, 30718709, 29162642, 20647261, 35119454, 35112029, 22328824, 29925512)
Eurofins Ntd Llc (ga)	RCV000085866	SCV000703956	pathogenic	not provided	2016-12-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763049	SCV000893530	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085866	SCV001210301	pathogenic	not provided	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change affects codon 256 of the ABCA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCA4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs62645944, gnomAD 0.02%). This variant has been observed in individual(s) with Stargardt disease (PMID: 10090887, 11726554, 15161829, 23695285). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99505). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10090887, 29162642). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074394	SCV001239973	pathogenic	Retinal dystrophy	2019-08-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085866	SCV001247758	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM2, PP3, PS3:Supporting
Institute of Medical Molecular Genetics, University of Zurich	RCV000408540	SCV001548123	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	RCV000085866	SCV001905562	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085866	SCV002019766	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003224863	SCV003921025	pathogenic	Cone-rod dystrophy 3	2023-03-28	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM3_STR,PM2_SUP,PP3
PreventionGenetics, part of Exact Sciences	RCV004529896	SCV004118979	pathogenic	ABCA4-related disorder	2023-08-11	criteria provided, single submitter	clinical testing	The ABCA4 c.768G>T variant is not predicted to result in an amino acid change (p.=). However, this variant is predicted to impact splicing (Alamut Visual v.2.11). This variant has been reported many times in the compound heterozygous state to be causative for severe autosomal recessive retinal disorders (see for examples Maugeri et al. 1999. PubMed ID: 10090887; Table S2 in Schulz et al. 2017. PubMed ID: 28118664; Table S1 in Birtel et al. 2018. PubMed ID: 29555955; Table S4 in Jespersgaard et al. 2019. PubMed ID: 30718709). Functional analysis using RT-PCR confirmed that this variant affects splicing and results in an abnormal splicing product (Sangermano et al. 2018. PubMed ID: 29162642). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94564350-C-A). Given the evidence, we interpret c.768G>T (p.=) as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV003993802	SCV004812585	pathogenic	Stargardt disease	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is a synonymous (silent) variant in exon 6 of ABCA4 that is predicted to impact splicing (SpliceAI, MaxEntScan, NNSplice). This prediction is confirmed by RT-PCR analysis of patient RNA and midi-gene generated from bacterial artificial chromosome. The assays demonstrated that the variant impacts splicing by cryptic donor site activiation in intron 6 producing a 35 bp frame-shift insertion (p.Leu257Valfs*17; PMID: 10090887, 29162642). The highest population minor allele frequency in gnomAD v2.1 is 0.02% (24/129,168 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been detected homozygous and compound heterozygous with a second pathogenic variant in multiple invidivuals with various retinal disorders, including retinitis pimentosa, Stargardt disease, and unscpeficied macular dystrophy (PMID: 10090887, 11726554, 28118664, 30718709, 33546218). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PM3_VeryStrong, PM2_Supporting, PP3.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074394	SCV005072250	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085866	SCV000118009	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000408540	SCV000599025	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678516	SCV000804588	pathogenic	Retinitis pigmentosa 19	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787525	SCV000926493	likely pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787526	SCV000926494	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085866	SCV001959558	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085866	SCV001966823	pathogenic	not provided		no assertion criteria provided	clinical testing