ClinVar Miner

Submissions for variant NM_004183.4(BEST1):c.653G>A (p.Arg218His) (rs281865239)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000086151 SCV000564701 likely pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing The R218H missense variant in the BEST1 gene has been reported previously in association with Best disease and Best macular dystrophy (Lotery et al., 2000; Booij et al., 2010; Katagiri et al., 2015). Alternate missense variants at the same residue (R218S, R218C, R218G) have also been reported in association with Best macular dystrophy (Bakall et al., 1999; Sodi et al., 2007). Furthermore, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server. The R218H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, R218H is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000086151 SCV001400544 pathogenic not provided 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 218 of the BEST1 protein (p.Arg218His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs281865239, ExAC 0.009%). This variant has been observed in several individuals and families affected with autosomal dominant Best vitelliform macular dystrophy (PMID: 10798642, 28559085, 30880907). It has also been observed in a family affected with autosomal recessive bestrophinopathy (PMID: 28481155); however, the role of this variant in autosomal recessive disease is unclear. ClinVar contains an entry for this variant (Variation ID: 99736). This variant has been reported to affect BEST1 protein function (PMID: 27193166). This variant disrupts the p.Arg218 amino acid residue in BEST1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10798642, 29781975). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Molecular Genetics, University of Zurich RCV001002892 SCV001548064 likely pathogenic Vitelliform macular dystrophy type 2 2021-01-30 criteria provided, single submitter clinical testing
Retina International RCV000086151 SCV000118295 not provided not provided no assertion provided not provided
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787544 SCV000926518 pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV001002892 SCV001160926 pathogenic Vitelliform macular dystrophy type 2 2019-06-23 no assertion criteria provided research

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