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

gnomAD frequency: 0.00001  dbSNP: rs281865239

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086151	SCV000564701	pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant to near complete loss of channel activity (PMID: 31836750); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30880907, 10798642, 30718709, 22448417, 27193166, 28481155, 26201355, 20381869, 28559085, 30498755, 31519547, 32239196, 31456290, 29781975, 34061021, 32416576, 38219857, 31836750, 36460718, 36729443)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000086151	SCV001400544	pathogenic	not provided	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 218 of the BEST1 protein (p.Arg218His). This variant is present in population databases (rs281865239, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy (PMID: 10798642, 28481155, 28559085, 30880907). ClinVar contains an entry for this variant (Variation ID: 99736). 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%. Experimental studies have shown that this missense change affects BEST1 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 2	2021-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086151	SCV002497126	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	BEST1: PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting
Retina International	RCV000086151	SCV000118295	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, 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 2	2019-06-23	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086151	SCV001958152	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086151	SCV001969826	pathogenic	not provided		no assertion criteria provided	clinical testing