rs199529046

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_004183.4(BEST1):c.602T>C(p.Ile201Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

BEST1
NM_004183.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.82

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 14 ACMG points.

PM1

In a strand (size 3) in uniprot entity BEST1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_004183.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 11-61956964-T-C is Pathogenic according to our data. Variant chr11-61956964-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61956964-T-C is described in Lovd as [Pathogenic]. Variant chr11-61956964-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-61956964-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST1	NM_004183.4 link	c.602T>C	p.Ile201Thr	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 link	c.602T>C	p.Ile201Thr	missense_variant	5/11	1	NM_004183.4	ENSP00000367282.4		O76090-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152048

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251360

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000735

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2024	Published functional studies suggest this variant results in partial loss of function, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 29063836); 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: 22422030, 10798642, 26333019, 17110374, 21273940, 22183385, 30609409, 31455904, 32239196, 33154968, 33039401, 35806438, 34996991, 32036094, 29063836) -
not provided, no classification provided	literature only	Retina International	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 201 of the BEST1 protein (p.Ile201Thr). This variant is present in population databases (rs199529046, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive bestrophinopathy (PMID: 22422030, 26333019). 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. This variant has been reported in individual(s) with sporadic or autosomal dominant Best vitelliform macular dystrophy (PMID: 10798642, 21109774); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 99726). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on BEST1 function (PMID: 17110374). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive bestrophinopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Dominant negative variants are associated with autosomal dominant disease (macular dystrophy, vitelliform, 2, MIM#153700; vitreoretinochoroidopathy, MIM#193220) while loss of function variants are associated with autosomal recessive disease (bestrophinopathy, autosomal recessive, MIM#611809; PMID: 29668979). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. This has been observed in individuals with dominant vitelliform macular dystrophy (PMID: 21273940). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated bestrophin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and has been observed in several compound heterozygous families with recessive vitelliform macular dystrophy (ClinVar, PMID: 22422030, PMID: 21273940). (SP) 0902 - This variant has moderate evidence for segregation with disease, where this variant was observed in three compound heterozygous siblings (PMID: 22422030). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 23, 2020	This sequence change is predicted to replace isoleucine with threonine at codon 201 of the BEST1 protein (p.Ile201Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in the bestrophin (RFP-TM) chloride channel domain. There is a moderate physicochemical difference between isoleucine and threonine. The variant is present in a large population cohort at a frequency of 0.007%, which is consistent with recessive disease (rs199529046, 19/282,720 alleles, 0 homozygotes in gnomAD v2.1 - PM2). The variant has been identified in the homozygous state (with a less severe phenotype) and compound heterozygote with a second pathogenic allele in multiple cases with autosomal recessive bestrophinopathy, and segregates with disease in at least one family (PMID: 21273940, 22422030, 27764019, 29063836 - PM3_Strong, PP1_Moderate). The variant causes reduced calcium-activated chloride channel function in in vitro functional assays (PMID: 17110374, 29063836 - PS3_Supporting). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM2, PP1_Moderate, PS3_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 02, 2016	The p.Ile201Thr variant in BEST1 has been reported in the compound heterozygous state in 4 individuals (3 family members and 1 unrelated individual). The 4 pati ents were affected with autosomal recessive bestrophinopathy. None of 3 heterozy gous family members were affected (Zhao 2012; Wivestad Jansson 2016 ). This var iant was also reported in the heterozygous state, in one patient with autosomal dominant Best macular dystrophy; however, insufficient data was present to suppo rt a dominant role or carrier phenotype (Lotery 2000). The p.Ile201Thr variant h as been identified in 7/121,390 of chromosomes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs199529046), a frequency low en ough to be consistent with a recessive carrier frequency. Computational analyses suggest that the p.Ile201Thr variant may impact the protein. In summary, additi onal data is needed to confirm the clinical significance of this variant; howeve r based upon the published data, we would classify this variant as likely pathog enic for autosomal recessive bestrophinopathy. -

Vitelliform macular dystrophy 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The BEST1 c.602T>C variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3, PP1, PS3. Based on this evidence we have classified this variant as Pathogenic. -

BEST1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The BEST1 c.602T>C (p.Ile201Thr) missense variant, also referred to as c.422T>C (p.Ile141Thr), has been reported in four studies in which it is found in a total of eight individuals from six unrelated families (Lotery et al. 2000; Kinnick et al. 2011; Zhao et al. 2012; Wivestad Jansson et al. 2016). Seven of the individuals are compound heterozygotes for the p.Ile201Thr variant, including three unrelated individuals with vitelliform macular dystrophy, three siblings with Best vitelliform macular dystrophy, and one individual with recessive bestrophinopathy. Another patient with Best vitelliform macular dystrophy was heterozygous for the p.Ile201Thr variant. The variant was also detected in a heterozygous state in four unaffected family members. The p.Ile201Thr variant has not been reported in the literature in patients with autosomal recessive retinitis pigmentosa or vitreoretinochoroidopathy. The p.Ile201Thr variant was absent from over 1500 control chromosomes but is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. Comparative protein modeling by Guziewicz et al. (2012) suggests that the p.Ile201Thr variant could induce conformational rearrangements and alter inter-residue interactions. Based on the collective evidence, the p.Ile201Thr variant is classified as likely pathogenic for BEST1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0060

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MVP

0.99

MPC

1.1

ClinPred

0.94

GERP RS

5.3

Varity_R

0.80

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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