ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro) (rs61751392)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085410 SCV000577606 pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing The L541P pathogenic variant in the ABCA4 gene have been reported numerous times in association with autosomal recessive cone-rod dystrophy and Stargardt disease (Rivera et al., 2000; Briggs et al. et al., 2001; Webster et al., 2001; Braun et al., 2013). In the literature, these two variants (L541P and A1038V) often occur together on the same allele, in cis, representing a complex L541P/A1038V allele, which is considered to represent a German founder mutation (Rivera et al., 2000; Briggs et al., 2001; Webster et al., 2001; Wiszniewski et al., 2005). However, personal communication with an external gene expert revealed that the L541P and A1038V variants have been identified by her lab on opposite alleles (in trans). In addition, both the L541P and A1038V have been observed independently in trans with another pathogenic variant in individuals with Stargardt disease (Rivera et al., 2000; Briggs et al., 2001; Burke et al., 2012). Functional studies demonstrate that both the L541P/A1038V complex allele as well as the L541P and A1038V variants independently result in reduced ATPase activity; however, the affect of A1038V is milder compared to that of L541P alone or the L541P/A1038V complex allele (Sun et al., 2000; Wiszniewski et al., 2005; Zhang et al., 2015). We interpret L541P as a pathogenic variant when present independently or when occurring together in cis with A1038V, which this variant is most commonly seen with.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085410 SCV000692637 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 Stargardt disease 1 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 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 541 of the ABCA4 protein (p.Leu541Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs61751392, ExAC 0.05%). This variant has been observed in many individuals affected with Stargardt disease, cone-rod dystrophy, or retinitis pigmentosa. While this variant is commonly found in cis with the pathogenic variant p.Ala1038Val (PMID: 10206579, 16103129, 19217903, 24509150), it has also been observed without p.Ala1038Val in affected individuals (PMID: 26593885, 28041643, 23755871, 11527935). ClinVar contains an entry for this variant (Variation ID: 99067). This variant has been reported to dramatically impair ABCA4 protein 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 Hypermetropia; Reduced visual acuity; Granular macular appearance 2019-03-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197075 SCV001367710 pathogenic Visual impairment 2016-01-01 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. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197159 SCV001367795 pathogenic Pigmentary retinopathy; Central scotoma; Macular degeneration; Blurred vision 2018-11-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197469 SCV001368222 uncertain significance Visual loss; Retinal dystrophy 2019-08-21 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: BP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199292 SCV001370369 pathogenic Macular degeneration; Visual field defect; Macular atrophy; Photoreceptor layer loss on macular OCT 2019-04-06 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP2,PP3. This variant was detected in homozygous state.
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 Stargardt disease 1 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

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