11-61956946-C-T

Position:

chr11-61956946-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_004183.4(BEST1):c.584C>T(p.Ala195Val) variant causes a missense change. The variant allele was found at a frequency of 0.000157 in 1,614,092 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. A195W?) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

BEST1
NM_004183.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:1O:1

Conservation

PhyloP100: 5.96

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:

BEST1 (HGNC:):

BEST1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a helix (size 14) in uniprot entity BEST1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_004183.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-61956944-GGC-GTGG is described in Lovd as [Likely_pathogenic].

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, max_spliceai, M_CAP, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

PP5

Variant 11-61956946-C-T is Pathogenic according to our data. Variant chr11-61956946-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61956946-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-61956946-C-T is described in Lovd as [Pathogenic]. Variant chr11-61956946-C-T is described in Lovd as [Pathogenic]. Variant chr11-61956946-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-61956946-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST1	NM_004183.4 linkuse as main transcript	c.584C>T	p.Ala195Val	missense_variant	5/11	ENST00000378043.9	NP_004174.1	O76090-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9 linkuse as main transcript	c.584C>T	p.Ala195Val	missense_variant	5/11	1	NM_004183.4	ENSP00000367282.4		O76090-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000262

AC:

AN:

251452

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00250

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000155

AC:

227

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00209

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000177

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2022	Published functional studies demonstrate a damaging effect on chloride channel function (Davidson et al., 2011; Lee et al., 2015); Observed in the heterozygous state in both sporadic and familial cases with clinical features of a BEST1-related bestrophinopathy, however familial segregation information was not included and it is unknown whether these individuals were screened for variants in other genes associated with the phenotype (Lotery et al., 2000; Boon et al., 2007; Kramer et al., 2003); 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: 18985398, 28687848, 32141364, 24560797, 21330666, 26720466, 17698758, 14517959, 23591405, 21809908, 21825197, 29555955, 29668979, 30498755, 30593719, 28559085, 21273940, 31766397, 31519547, 32100970, 33302512, 34373720, 33090715, 33691693, 10798642) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 195 of the BEST1 protein (p.Ala195Val). This variant is present in population databases (rs200277476, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive retinopathy or bestrophinopathy (PMID: 18985398, 20927214, 21273940, 21809908, 21825197, 25489231, 26201355, 28687848, 29555955). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99725). 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: 2133066, 24560797, 26720466, 29668979). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive bestrophinopathy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 20, 2020	This sequence change is predicted to replace alanine with valine at codon 195 of the BEST1 protein (p.Ala195Val). The alanine residue is moderately conserved (100 vertebrates, UCSC), and located in the bestrophin, RFP-TM, chloride channel domain (Uniprot). There is a moderate physicochemical difference between alanine and valine. The variant is present in a large population cohort at a frequency of 0.025% (rs200277476, 71/282,812 alleles, 1 homozygote in gnomAD 2.1), with an East Asian population frequency of 0.2% (47/19,952 alleles, 1 homozygote). The variant has been identified with a second pathogenic allele in multiple individuals with autosomal recessive bestrinopathy (PM3_VeryStrong; PMID: 28687848, 30498755, 30593719), and segregates with disease in at least one family (PP1; PMID: 26720466). The variant significantly reduces BEST1 function, which is fully ablated when co-transfected with other recessive variants in in vitro assays (PS3_Supporting; PMID: 21330666, 26720466). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PP1, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Bestrophinopathy, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => For recessive disorders, detected in trans with a likely pathogenic variant (PMID:21273940). PP1-Moderate => PP1 upgraded in strength to Moderate . PS3 => Well-established functional studies show a deleterious effect (PMID:26720466) (PMID:21330666). -

Retinal dystrophy

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 29, 2019	- -

Vitelliform macular dystrophy 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Vitelliform macular dystrophy 2;C2750789:Retinitis pigmentosa 50;C3888099:Autosomal dominant vitreoretinochoroidopathy;C3888198:Autosomal recessive bestrophinopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 03, 2022

- -

BEST1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2024

The BEST1 c.584C>T variant is predicted to result in the amino acid substitution p.Ala195Val. This variant was reported in multiple individuals with BEST1-related retinal disease (autosomal recessive: Davidson et al. 2011. PubMed ID: 21330666; Borman et al. 2011. PubMed ID: 21825197; Lee et al. 2015 et al. PubMed ID: 26720466). Heterozygous individuals have been reported to be both affected (Supplementary table 1, Glöckle et al. 2013. PubMed ID: 23591405; Liu et al. 2020. PubMed ID: 33090715) and unaffected (Borman et al. 2011. PubMed ID: 21825197). This variant is reported in 0.24% of alleles in individuals of East Asian descent in gnomAD. Functional studies have demonstrated that this variant does not impact protein localization (Johnson et al. 2014. PubMed ID: 24560797), however, the variant has been shown in vitro to reduce channel conductance (Davidson et al. 2011. PubMed ID: 21330666). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.83

MVP

0.99

MPC

0.88

ClinPred

0.28

GERP RS

4.3

Varity_R

0.86

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.51

Position offset: -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