ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro)

gnomAD frequency: 0.00017  dbSNP: rs61751392
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 24
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000085410 SCV000225507 uncertain significance not provided 2016-11-16 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408513 SCV000281824 pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085410 SCV000577606 pathogenic not provided 2022-08-10 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 (Sun et al., 2000; Wiszniewski et al., 2005; Zhang et al., 2015); 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: 9781034, 28118664, 29847635, 19217903, 19074458, 24713488, 24509150, 10958763, 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, 34315337, 11017087, 11527935)
CeGaT Center for Human Genetics Tuebingen RCV000085410 SCV000692637 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized 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, Molecular Genetics and Genomics,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.
Invitae RCV000085410 SCV001234647 pathogenic not provided 2021-12-08 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. 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,University Medical Centre Ljubljana 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, University Hospital Tübingen RCV000085410 SCV001447239 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear 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.
Institute of Human Genetics, University of Leipzig Medical Center 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, University Hospital Muenster 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
Retina International RCV000085410 SCV000117547 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504750 SCV000598938 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000408513 SCV000598939 likely pathogenic Severe early-childhood-onset retinal dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505133 SCV000598940 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504750 SCV000926446 likely pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787481 SCV000926447 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787482 SCV000926448 likely pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV000787481 SCV001160865 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research
PerkinElmer Genomics RCV000085410 SCV002020364 pathogenic not provided 2021-03-03 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.