Submissions for variant NM_004183.4(BEST1):c.400C>G (p.Leu134Val)

gnomAD frequency: 0.00001  dbSNP: rs753614067

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001060439	SCV001225126	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 427886). This missense change has been observed in individuals with autosomal recessive bestrophinopathy (PMID: 29507198, 32239196, 33302512). This variant has been reported in individual(s) with autosomal dominant Best vitelliform macular dystrophy (PMID: 17287362); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs753614067, gnomAD 0.008%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the BEST1 protein (p.Leu134Val).
CeGaT Center for Human Genetics Tuebingen	RCV001060439	SCV001245798	pathogenic	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000491340	SCV002549761	likely pathogenic	Autosomal recessive bestrophinopathy	2022-03-28	criteria provided, single submitter	clinical testing	This individual is homozygous for the c.400C>G variant in the BEST1 gene, which results in the amino acid substitution of leucine to valine at residue 134, p.(Leu134Val). This variant has been reported in the gnomAD v2.1.1 browser (http://gnomad.broadinstitute.org accessed: 28/03/2022) with a very low allele frequency of 0.003% (5 out of 150,438 alleles). All five individuals in gnomAD are heterozygous for the variant, there are no individuals in gnomAD that are homozygous for this variant. This variant has been previously reported in multiple individuals with autosomal recessive bestrophinopathy as either a homozygous variant or in compound heterozygosity with other disease-causing BEST1 variants (Nowomiejska et al 2021 PMID: 34327816; Hufendiek et al 2020 PMID: 33302512; Shah et al 2020 PMID: 32239196; Deak et al 2019 PMID: 29215532; Guziewicz et al 2018 PMID: 29507198). In silico analysis of pathogenicity (through Alamut Visual v2.13) using PolyPhen2, SIFT and MutationTaster is inconclusive regarding this change; PolyPhen2 and MutationTaster predict the variant to be deleterious to the protein, whereas SIFT predicts the variant to be tolerated. This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM2, PM3_strong, PP4).
Laboratorio de Imunogenetica e Histocompatibilidade, Universidade Federal do Parana	RCV000491340	SCV000502995	pathogenic	Autosomal recessive bestrophinopathy	2015-01-25	no assertion criteria provided	research	The variant c.400C>G together with c.422G>A believed be causative of Bestrophinopathy autossomic recessive (BAR). It was first related of this combination of the two variants related to BAR.