Submissions for variant NM_004183.4(BEST1):c.652C>T (p.Arg218Cys)

dbSNP: rs281865238

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000086150	SCV000231676	likely pathogenic	not provided	2014-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000086150	SCV000490429	pathogenic	not provided	2020-12-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: while the protein possessing the R218C variant still localized to the plasma membrane, it failed to increase the Ca2+ dependent anion permeability in transfected cells (Milenkovic et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with an additional BEST1 variant in a patient with autosomal recessive bestrophinopathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Luo et al., 2019); This variant is associated with the following publications: (PMID: 28687848, 29555955, 21878505, 23825107, 25489231, 29668979, 9700209, 30593719, 31570112, 31519547, 32239196, 29288639, 23213274, 29781975, 22633354)
Fulgent Genetics, Fulgent Genetics	RCV000763263	SCV000893901	pathogenic	Autosomal recessive bestrophinopathy; Vitelliform macular dystrophy 2; Autosomal dominant vitreoretinochoroidopathy; Retinitis pigmentosa 50	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000086150	SCV001205165	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the BEST1 protein (p.Arg218Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Best vitelliform macular dystrophy (PMID: 28687848, 29781975). This variant has been reported in individual(s) with autosomal recessive bestrophinopathy (PMID: 30593719); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 99735). 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: 21878505, 23825107). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073491	SCV001239034	pathogenic	Retinal dystrophy	2019-03-31	criteria provided, single submitter	clinical testing
Retina International	RCV000086150	SCV000118294	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787543	SCV000926517	likely pathogenic	Vitelliform macular dystrophy 2	2018-04-01	no assertion criteria provided	research