Submissions for variant NM_004183.4(BEST1):c.37C>T (p.Arg13Cys)

gnomAD frequency: 0.00003  dbSNP: rs886041141

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000311174	SCV000329110	likely pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in patients with clinical features of autosomal dominant vitelliform macular dystrophy in published literature (Kinnick et al., 2011; Abdalla et al., 2017; Dalvin et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21273940, 28728185, 27120116, 31725702, 34012682, 33512609, 29555955)
Blueprint Genetics	RCV001075804	SCV001241439	pathogenic	Retinal dystrophy	2019-07-11	criteria provided, single submitter	clinical testing
Invitae	RCV000311174	SCV001382710	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg13 amino acid residue in BEST1. Other variant(s) that disrupt this residue have been observed in individuals with BEST1-related conditions (PMID: 10331951, 21273940; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 279701). This missense change has been observed in individuals with autosomal dominant BEST1-related conditions (PMID: 21273940, 29555955; Invitae). This variant has been reported in individual(s) with autosomal recessive retinal disease (Invitae); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the BEST1 protein (p.Arg13Cys).
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376382	SCV001573502	uncertain significance	Vitelliform macular dystrophy 2	2021-04-08	criteria provided, single submitter	research	The BEST1 c.37C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Genetics and Molecular Pathology, SA Pathology	RCV001376382	SCV002556739	likely pathogenic	Vitelliform macular dystrophy 2	2021-08-16	criteria provided, single submitter	clinical testing	There are multiple RNA isoforms for the BEST1 gene and this exon is not expressed in all isoforms. Other isoforms, which do not transcribe this exon, are expressed at a higher level.