ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2546T>C (p.Val849Ala) (rs61749435)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000085485 SCV001105326 benign not provided 2020-12-03 criteria provided, single submitter clinical testing
Mendelics RCV000986366 SCV001135354 uncertain significance Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074506 SCV001240093 uncertain significance Retinal dystrophy 2017-12-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286435 SCV001473003 uncertain significance none provided 2019-12-10 criteria provided, single submitter clinical testing The ABCA4 c.2546T>C; p.Val849Ala variant (rs61749435) is reported in the literature in multiple individuals affected with Stargardt disease or related retinopathies, although these studies do not agree on the variant’s clinical significance (Cideciyan 2004, Fujinami 2019, Kersten 2018, Lee 2015, Thiadens 2012, Webster 2001). Several affected individuals with the p.Val849Ala variant carried an additional pathogenic variant (Fujinami 2019, Cideciyan 2004), although one individual was found with two other pathogenic ABCA4 variants that may have explained this individual’s disease (Lee 2015). The p.Val849Ala variant is found in the African population with an overall allele frequency of 1.3% (324/24946 alleles, including five homozygotes) in the Genome Aggregation Database. The valine at codon 849 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val849Ala variant is uncertain at this time. References: Cideciyan AV et al. Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence. Hum Mol Genet. 2004 Mar 1;13(5):525-34. Fujinami K et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol. 2019 Mar;103(3):390-397. Kersten E et al. Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration. Clin Genet. 2018 Dec;94(6):569-574. Lee K et al. High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting. Am J Ophthalmol. 2015 Aug;160(2):354-363.e9. Thiadens AA et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012 Apr;119(4):819-26. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89.
Retina International RCV000085485 SCV000117622 not provided not provided no assertion provided not provided

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