chr11-61955892-G-A

Position:

chr11-61955892-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_004183.4(BEST1):c.422G>A(p.Arg141His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,550,476 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

BEST1
NM_004183.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 9.83

Variant links:

Genes affected

BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]

BEST1 links:

LOC107984334 (HGNC:):

LOC107984334 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a helix (size 24) in uniprot entity BEST1_HUMAN there are 36 pathogenic changes around while only 0 benign (100%) in NM_004183.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-61955891-C-A is described in Lovd as [Pathogenic].

PP5

Variant 11-61955892-G-A is Pathogenic according to our data. Variant chr11-61955892-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61955892-G-A is described in Lovd as [Pathogenic]. Variant chr11-61955892-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-61955892-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-61955892-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST1	NM_004183.4 linkuse as main transcript	c.422G>A	p.Arg141His	missense_variant	4/11	ENST00000378043.9	NP_004174.1
LOC107984334	XR_001748245.2 linkuse as main transcript	n.2802C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9 linkuse as main transcript	c.422G>A	p.Arg141His	missense_variant	4/11	1	NM_004183.4	ENSP00000367282	P1	O76090-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000521

AC:

AN:

149610

Hom.:

AF XY:

0.000491

AC XY:

AN XY:

79498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000601

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.000283

AC:

395

AN:

1398106

Hom.:

Cov.:

AF XY:

0.000273

AC XY:

188

AN XY:

689626

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.000358

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00256

Gnomad4 NFE exome

AF:

0.000227

Gnomad4 OTH exome

AF:

0.000259

GnomAD4 genome

AF:

0.000315

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000505

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000248

AC:

ExAC

AF:

0.000139

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2015	The R141H variant in the BEST1 gene has been reported previously in association with Best macular dystrophy (Kramer et al., 2000). This variant was not observed at any significant frequency in either the NHLBI Exome Sequencing Project or the 1000 Genomes Project. The R141H substitution occurs at a position that is conserved across species. Functional in vitro studies have demonstrated that the R141H protein is mislocalized, prematurely degraded, and has significantly reduced chloride conductance relative to the wild-type protein (Davidson et al., 2011; Johnson et al., 2014). We interpret the R141H variant as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	BEST1: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the BEST1 protein (p.Arg141His). This variant is present in population databases (rs121918284, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive BEST-related disorders (PMID: 16754206, 21809908, 23290749, 26333019). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2740). 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: 18179881, 21330666, 26200502, 27519691). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Autosomal recessive bestrophinopathy

Pathogenic:3

Pathogenic, no assertion criteria provided	phenotyping only	Laboratorio de Imunogenetica e Histocompatibilidade, Universidade Federal do Parana	Jan 25, 2015	The variant was found together with c.400C>G. Both are believed are causative of Bestrophinopathy autosomal recessive (BAR). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -

Vitelliform macular dystrophy 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

BEST1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The BEST1 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been reported in the compound heterozygous state and segregates in several families with BEST-related disorders (Krämer et al. 2000. PubMed ID: 10854112; Burgess et al. 2008. PubMed ID: 18179881; Borman et al. 2011. PubMed ID: 21825197). Functional studies suggested that this variant causes mislocalization and misfolding of the protein and reduced channel activity (Davidson et al. 2011. PubMed ID: 21330666). The amino acid residue p.Arg141 of the BEST1 protein has been highly conserved during evolution. This variant is reported in 0.33% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 15, 2019

- -

Stargardt disease

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.8

H;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.90

MVP

1.0

MPC

1.1

ClinPred

0.59

GERP RS

5.1

Varity_R

0.95

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over