Submissions for variant NM_004183.4(BEST1):c.103G>A (p.Glu35Lys)

dbSNP: rs886041142

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000356527	SCV000329111	likely pathogenic	not provided	2018-10-18	criteria provided, single submitter	clinical testing	The E35K variant in the BEST1 gene has been reported previously in an individual with autosomal recessive bestrophinopathy with no second disease-causing variant identified (Tian et al., 2017). The E35K variant has also been reported in an individual with best macular dystrophy, although further information was not provided (Maia-Lopes et al., 2008). The E35K variant is not observed in large population cohorts (Lek et al., 2016). The E35K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E35K as a likely pathogenic variant.
Invitae	RCV000356527	SCV001558555	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 35 of the BEST1 protein (p.Glu35Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive Best disease (PMID: 28559085, 31766397, 34015078). ClinVar contains an entry for this variant (Variation ID: 279702). 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. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV003152701	SCV003841651	likely pathogenic	Autosomal recessive bestrophinopathy	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279702). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003417872	SCV004107813	likely pathogenic	BEST1-related condition	2023-07-17	criteria provided, single submitter	clinical testing	The BEST1 c.103G>A variant is predicted to result in the amino acid substitution p.Glu35Lys. This variant has been reported in the homozygous state and in the heterozygous state along with a second BEST1 variant in individuals with autosomal recessive Best macular dystrophy (Table S1 in Stone et al. 2017. PubMed ID: 28559085; Habibi et al. 2019. PubMed ID: 31766397; Pfister et al. 2021. PubMed ID: 34015078). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic for autosomal recessive disease.