ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4793C>A (p.Ala1598Asp)

gnomAD frequency: 0.00003  dbSNP: rs61750155
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408465 SCV000281906 likely pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085674 SCV000511901 pathogenic not provided 2022-03-10 criteria provided, single submitter clinical testing Published functional studies demonstrate A1598D results in reduced basal activity, supporting a damaging effect (Curtis et al., 2020); This variant is associated with the following publications: (PMID: 27014590, 23105016, 20696155, 10958761, 22025579, 28118664, 29178665, 28365912, 19074458, 25525159, 26103963, 29925512, 28559085, 32845050, 31589614, 32619608, 34426522, 32783370)
Invitae RCV000085674 SCV001213077 pathogenic not provided 2021-09-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 1598 of the ABCA4 protein (p.Ala1598Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs61750155, ExAC 0.009%). This missense change has been observed in individual(s) with retinal disease (PMID: 10958761, 19074458, 23105016, 28559085). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99321). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala1598 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26161775), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074177 SCV001239747 pathogenic Retinal dystrophy 2019-02-20 criteria provided, single submitter clinical testing
3billion RCV001808326 SCV002058292 pathogenic Retinitis pigmentosa 19 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099321, PMID:10958761, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PM3_S). A different missense change at the same codon has been reported to be associated with ABCA4 related disorder (PMID:26161775, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.685, 3CNET: 0.955, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen RCV000085674 SCV002544292 likely pathogenic not provided 2022-05-01 criteria provided, single submitter clinical testing
Retina International RCV000085674 SCV000117814 not provided not provided no assertion provided not provided
NEI Ophthalmic Genomics Laboratory,National Institutes of Health RCV000085674 SCV000119179 not provided not provided no assertion provided not provided
Sharon lab,Hadassah-Hebrew University Medical Center RCV001002825 SCV001160842 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research
Faculty of Health Sciences,Beirut Arab University RCV001257846 SCV001434613 pathogenic Autosomal recessive retinitis pigmentosa 2012-10-26 no assertion criteria provided literature only
PerkinElmer Genomics RCV000085674 SCV002019755 pathogenic not provided 2021-11-08 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000085674 SCV002037365 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000085674 SCV002037810 likely pathogenic not provided no assertion criteria provided clinical testing

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