ClinVar Miner

Submissions for variant NM_004183.4(BEST1):c.388C>A (p.Arg130Ser)

gnomAD frequency: 0.00003  dbSNP: rs750102662
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001236697 SCV001409431 pathogenic not provided 2024-01-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 130 of the BEST1 protein (p.Arg130Ser). This variant is present in population databases (rs750102662, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive bestrophinopathy (PMID: 21269699, 21738390, 32141364). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant Best disease (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 962776). 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 BEST1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg130 amino acid residue in BEST1. Other variant(s) that disrupt this residue have been observed in individuals with BEST1-related conditions (PMID: 25489231), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Molecular Genetics, University of Zurich RCV001352945 SCV001548012 likely pathogenic Autosomal recessive bestrophinopathy 2021-01-30 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003393904 SCV004121162 pathogenic BEST1-related condition 2023-05-01 criteria provided, single submitter clinical testing The BEST1 c.388C>A variant is predicted to result in the amino acid substitution p.Arg130Ser. This variant has been reported in the homozygous state or in the heterozygous state with a second BEST1 variant in several individuals with autosomal recessive bestrophinopathy (Meunier et al. 2011. PubMed ID: 21269699; Table 2, Del Pozo-Valero et al. 2022. PubMed ID: 35119454; Table S4: Patient RPN-363, Rodríguez-Muñoz et al. 2020. PubMed ID: 32036094; Supplementary Table, Zanolli et al. 2020. PubMed ID: 32141364; Piñeiro-Gallego T et al. 2011. PubMed ID: 21738390; ID167 Table 1A, Maggi et al. 2021. PubMed ID: 33546218). Additionally, a different substitution impacting the same amino acid (p.Arg130Leu) has also been reported in a family with autosomal recessive bestrophinopathy in the homozygous state (Family H, Tian et al. 2014. PubMed ID: 25489231). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-61723330-C-A). This variant is interpreted as pathogenic.

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