Total submissions: 31
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute of Human Genetics, |
RCV000408513 | SCV000281824 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2016-01-01 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000085410 | SCV000577606 | pathogenic | not provided | 2024-12-09 | criteria provided, single submitter | clinical testing | Functional studies demonstrate that the p.(L541P)/p.(A1038V) complex allele as well as the p.(L541P) and p.(A1038V) variants independently result in reduced ATPase activity; however, the affect of p.(A1038V) is milder compared to that of p.(L541P) alone or the p.(L541P)/p.(A1038V) complex allele (PMID: 11017087, 16103129, 25712131); 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: 37510321, 37498587, 35120629, 35260635, 31964843, 36460718, 32307445, 36672815, 29701254, 33749171, 34321860, 34906470, 9781034, 28118664, 29847635, 38003421, 37734845, 31429209, 32531858, 19217903, 19074458, 24713488, 24509150, 25712131, 10958761, 11328725, 26593885, 28041643, 16103129, 29555955, 29186038, 29068140, 30204727, 29925512, 30718709, 30653986, 32581362, 31573552, 33851411, 32619608, 32783370, 32037395, 32141364, 30643219, 33369172, 29114839, 28559085, 31456290, 35836572, 35119454, 34315337, 11017087, 11527935, 10958763, 22312191, 23918662) |
Ce |
RCV000085410 | SCV000692637 | pathogenic | not provided | 2024-03-01 | criteria provided, single submitter | clinical testing | ABCA4: PM3:Very Strong, PM1, PM2, PP3, PS3:Supporting |
Laboratory for Molecular Medicine, |
RCV000787481 | SCV000967650 | pathogenic | Stargardt disease | 2018-08-14 | criteria provided, single submitter | clinical testing | The p.Leu541Pro variant in ABCA4 has been reported in the compound heterozygous state in >4 individuals with Stargardt disease or related retinal dystrophy and as a part of the Leu541Pro/Ala1038Val complex allele (in cis with p.Ala1038Val) in >25 compound heterozygous or homozygous individuals with Stargardt disease or related retinal dystrophy (Rozet 1998, Rivera 2000, Webster 2001, Briggs 2001, Gerth 2002, Hargitai 2005, Cideciyan 2009, Braun 2013, Fujinami 2013, Bertelse n 2014, Audere 2015, Fakin 2016, Lee 2016, Carss 2017, Porto 2017, Salles 2017) . The p.Leu541Pro variant segregated with disease in 1 compound heterozygous sib ling (Lee 2016), and the Leu541Pro/Ala1038Val complex allele segregated with dis ease in >12 affected relatives (Rivera 2000, Wiszniewski 2005, Braun 2013, Sall es 2017). The p.Leu541Pro variant has been identified in 0.07% (17/25792) of Fin nish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs61751392) and has also been reported in ClinVar (Variatio n ID: 99067). A mouse model of the complex allele resulted in a Stargardt-like p henotype in homozygous mice (Zhang 2015). Additional functional studies demonstr ated that the p.Leu541Pro and p.A1038V alleles each impact functional activity a nd that the Leu541Pro/Ala1038Val complex allele is more severe, resembling a com plete loss of activity (Sun 2000, Wiszniewski 2005, Zhang 2015). In summary, the p.Leu541Pro variant meets criteria to be classified as pathogenic for Stargardt disease in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VerySt rong; PS3_Supporting; PP3. |
Mendelics | RCV000408513 | SCV001135359 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2019-05-28 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV001002385 | SCV001160303 | pathogenic | not specified | 2019-03-04 | criteria provided, single submitter | clinical testing | The ABCA4 c.1622T>C; p.Leu541Pro variant (rs61751392), is reported in the literature in numerous individuals affected with Stargardt disease, retinitis pigmentosa, or other related retinopathies (Briggs 2001, Rivera 2000, Rozet 1998, Wiszniewski 2005). This variant is commonly reported in cis to another missense variant, p.Ala1038Val, and the [p.Leu541Pro; p.Ala1038Val] complex variant has been reported in the homozygous and compound heterozygous states in multiple affected individuals (Briggs 2001, Rivera 2000, Wiszniewski 2005). Functional studies suggest that p.Leu541Pro, independent of p.Ala1038Val, causes protein misfolding, mislocalization, and reduced ATP binding and hydrolysis (Sun 2000, Wiszniewski 2005, Zhang 2015). The p.Leu541Pro variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 99067) and is found in the general population with an overall allele frequency of 0.02% (46/282812 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Briggs CE et al. Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2229-36. Rivera A et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Oct;67(4):800-13. Rozet JM et al. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Eur J Hum Genet. 1998 May-Jun;6(3):291-5. Sun H et al. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet. 2000 Oct;26(2):242-6. Wiszniewski W et al. ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum Mol Genet. 2005 Oct 1;14(19):2769-78. Zhang N et al. Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Hum Mol Genet. 2015 Jun 1;24(11):3220-37. |
Labcorp Genetics |
RCV000085410 | SCV001234647 | pathogenic | not provided | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 541 of the ABCA4 protein (p.Leu541Pro). This variant is present in population databases (rs61751392, gnomAD 0.07%). This missense change has been observed in individuals with Stargardt disease, cone-rod dystrophy, or retinitis pigmentosa (PMID: 10206579, 11527935, 16103129, 19217903, 23755871, 24509150, 26593885, 28041643). ClinVar contains an entry for this variant (Variation ID: 99067). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 11017087, 25712131, 29847635). For these reasons, this variant has been classified as Pathogenic. |
Blueprint Genetics | RCV000505133 | SCV001240473 | pathogenic | Retinal dystrophy | 2019-08-07 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV001196126 | SCV001366613 | pathogenic | Age related macular degeneration 2 | 2018-11-23 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. |
Institute of Medical Genetics and Applied Genomics, |
RCV000085410 | SCV001447239 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Ocular Genomics Institute, |
RCV000408513 | SCV001573323 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2021-04-08 | criteria provided, single submitter | research | The ABCA4 c.1622T>C 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: PS3, PM2, PM3, PP3, PP5. Based on this evidence we have classified this variant as Pathogenic. |
Revvity Omics, |
RCV000085410 | SCV002020364 | pathogenic | not provided | 2023-09-22 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000787482 | SCV002044300 | likely pathogenic | Macular dystrophy | 2021-11-22 | criteria provided, single submitter | clinical testing | This variant was identified aspotentially compound heterozygous with NM_000350.3:c.3113C>T and NM_000350.3:c.5882G>A. Criteria applied: PM3_VSTR, PS3_MOD, PP3 |
3billion | RCV000408513 | SCV002059063 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 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: VCV000099067, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983, 3CNET: 0.996, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000163, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
Institute of Human Genetics, |
RCV000408513 | SCV002496135 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2019-01-08 | criteria provided, single submitter | clinical testing | ACMG categories: PS1,PS3,PP2,PP3,PP5 |
MGZ Medical Genetics Center | RCV000408513 | SCV002581779 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2022-08-11 | criteria provided, single submitter | clinical testing | |
Genetics and Molecular Pathology, |
RCV000505133 | SCV002761766 | pathogenic | Retinal dystrophy | 2021-02-24 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000408513 | SCV003804642 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2023-01-31 | criteria provided, single submitter | clinical testing | This variant was identified together with NM_000350.3:c.3113C>T, NM_000350.3:c.2588G>C, NM_000350.3:c.5693G>A and NM_000350.3:c.1411G>A. Criteria applied: PM3_VSTR, PS3_MOD, PP3 |
Institute of Human Genetics, |
RCV000505133 | SCV005068533 | pathogenic | Retinal dystrophy | 2023-01-01 | criteria provided, single submitter | clinical testing | |
Clinical Genetics Laboratory, |
RCV000085410 | SCV005199084 | pathogenic | not provided | 2022-07-13 | criteria provided, single submitter | clinical testing | |
North West Genomic Laboratory Hub, |
RCV000408513 | SCV005627611 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2023-12-11 | criteria provided, single submitter | clinical testing | PM2_Mod PM3_Str PP3_Mod PS3_Str |
Retina International | RCV000085410 | SCV000117547 | not provided | not provided | no assertion provided | not provided | ||
Eurofins Ntd Llc |
RCV000085410 | SCV000225507 | uncertain significance | not provided | 2016-11-16 | flagged submission | clinical testing | |
NIHR Bioresource Rare Diseases, |
RCV000504750 | SCV000598938 | likely pathogenic | Retinitis pigmentosa | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000408513 | SCV000598939 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000505133 | SCV000598940 | likely pathogenic | Retinal dystrophy | 2015-01-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000504750 | SCV000926446 | likely pathogenic | Retinitis pigmentosa | 2018-04-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000787481 | SCV000926447 | likely pathogenic | Stargardt disease | 2018-04-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000787482 | SCV000926448 | likely pathogenic | Macular dystrophy | 2018-04-01 | no assertion criteria provided | research | |
Sharon lab, |
RCV000787481 | SCV001160865 | pathogenic | Stargardt disease | 2019-06-23 | no assertion criteria provided | research | |
Prevention |
RCV004528784 | SCV004106705 | pathogenic | ABCA4-related disorder | 2024-09-06 | no assertion criteria provided | clinical testing | The ABCA4 c.1622T>C variant is predicted to result in the amino acid substitution p.Leu541Pro. This variant has been reported as causative for autosomal recessive Stargardt Disease (STGD) (see for example Rozet et al. 1998. PubMed ID: 9781034; Wiszniewski et al. 2005. PubMed ID: 16103129). This variant is frequently detected on the same chromosome (in cis) with another ABCA4 variant, c.3113C>T (p.Ala1038Val), as the complex allele p.[Leu541Pro;Ala1038Val] in patients with autosomal recessive retinal dystrophy (Burke et al. 2012. PubMed ID: 22312191; Cella et al. 2009. PubMed ID: 19217903; Wiszniewski et al. 2005. PubMed ID: 16103129; Klevering et al. 2004. PubMed ID: 15494742). The complex allele is reported to cause a more severe phenotype than either variant individually (Zhang et al. 2015. PubMed ID: 25712131). This variant is reported in 0.068% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99067/). Given all the evidence, we interpret c.1622T>C (p.Leu541Pro) both alone and as part of the complex allele p.[Leu541Pro;Ala1038Val] as pathogenic. |