ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) (rs61750130)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078666 SCV000110525 pathogenic not provided 2013-08-09 criteria provided, single submitter clinical testing
GeneDx RCV000078666 SCV000329047 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing The P1380L variant has been published previously in the homozygous or compound heterozygous state in multiple individuals with ABCA4-related disorders (Briggs et al., 2001; Oh et al., 2004; Cideciyan et al., 2009). P1380L is observed in 20/10136 (0.197%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we consider this variant to be pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454310 SCV000538009 pathogenic Mandibulofacial dysostosis with mental deficiency 2015-07-24 criteria provided, single submitter clinical testing This variant has been observed, either as homozygous (Hwang JC et al., 2009) or compound heterozygous (Lewis RA et al., 1999) in individuals who have been diagnosed with Stargardt disease. It co-segregates with disease and was found in trans with the known pathogenic variant, G1961E (Duncker T et al., 2015). In the protein, it is present in the helical transmembrane domain 7 and is close to the nucleotide binding domain-1. Studies in HEK 293 cells showed that, compared with wild-type, the protein yield and ATP-binding capacity of this variant was reduced (Sun H et al., 2000). Finally, multiple computational algorithms predict this variant to be deleterious and its frequency in the population databases (1000 Genomes, Exome Sequencing Project [ESP] and ExAC) is either absent or very low. Therefore, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
Fulgent Genetics,Fulgent Genetics RCV000763044 SCV000893525 pathogenic Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778258 SCV000914430 pathogenic ABCA4-Related Disorders 2018-08-21 criteria provided, single submitter clinical testing The ABCA4 c.4139C>T (p.Pro1380Leu) missense variant has been reported in at least ten studies in which it is found in at least 38 individuals with either Stargardt disease (STGD), cone-rod dystrophy or age related macular degeneration including in five individuals in a homozygous state, at least 29 in a compound heterozygous state, and four individuals in a heterozygou state (Shroyer et al. 1999; Lewis et al. 1999; Shroyer et al. 2001; Briggs et al. 2001; Oh et al. 2004; Fingert et al. 2006; Hwang et al. 2009; Cideciyan et al. 2009; Chacón-Camacho et al. 2013; Duncker et al. 2015). The p.Pro1380Leu variant has been shown to segregate with STGD disease in at least three families (Lewis et al. 1999; Shroyer et al. 2001; Cideciyan et al. 2009). The variant has not been reported in association with retinitis pigmentosa. The p.Pro1380Leu variant was absent from at least 895 controls and is reported at a frequency of 0.001973 in the Ashkenazi Jewish population of the Genome Aggregation Database. In vitro analysis in HEK-293 cells demonstrated that the p.Pro1380Leu variant resulted in reduced expression of the protein and defective ATP binding (Sun et al. 2000). Based on the collective evidence, the p.Pro1380Leu variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000078666 SCV001211297 pathogenic not provided 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1380 of the ABCA4 protein (p.Pro1380Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs61750130, ExAC 0.03%). This variant has been observed to segregate with Stargardt disease in multiple families (PMID: 9973280, 28559085). ClinVar contains an entry for this variant (Variation ID: 7904). This variant has been reported to affect ABCA4 protein function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075868 SCV001241509 pathogenic Retinal dystrophy 2019-08-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078666 SCV001249460 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
OMIM RCV000008362 SCV000028570 pathogenic Stargardt disease 1 2006-05-01 no assertion criteria provided literature only
OMIM RCV000023139 SCV000044430 risk factor MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO 2006-05-01 no assertion criteria provided literature only
Retina International RCV000078666 SCV000117745 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000008362 SCV000598970 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787498 SCV000926464 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV000787498 SCV001160848 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

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