11-61957402-C-T

Variant names:

• chr11-61957402-C-T
• rs281865238
• NM_004183.4:c.652C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004183.4(BEST1):​c.652C>T​(p.Arg218Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,676 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 2.29
• Publications: 48 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant vitreoretinochoroidopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• vitelliform macular dystrophy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal recessive bestrophinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 50

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• adult-onset foveomacular vitelliform dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• MRCS syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC107984334 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004183.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-61957403-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 0.61695 (below the threshold of 3.09). Trascript score misZ: 0.88358 (below the threshold of 3.09). GenCC associations: The gene is linked to vitelliform macular dystrophy 2, MRCS syndrome, autosomal recessive bestrophinopathy, autosomal dominant vitreoretinochoroidopathy, retinitis pigmentosa, retinitis pigmentosa 50, inherited retinal dystrophy, adult-onset foveomacular vitelliform dystrophy, nanophthalmia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-61957402-C-T is Pathogenic according to our data. Variant chr11-61957402-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEST1	NM_004183.4	c.652C>T	p.Arg218Cys	missense_variant	Exon 6 of 11	ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9	c.652C>T	p.Arg218Cys	missense_variant	Exon 6 of 11	1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461676 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000511 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

Jun 17, 2014

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the BEST1 protein (p.Arg218Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Best vitelliform macular dystrophy (PMID: 28687848, 29781975). This variant has been reported in individual(s) with autosomal recessive bestrophinopathy (PMID: 30593719); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 99735). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 21878505, 23825107). For these reasons, this variant has been classified as Pathogenic. -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 16, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: while the protein possessing the R218C variant still localized to the plasma membrane, it failed to increase the Ca2+ dependent anion permeability in transfected cells (Milenkovic et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with an additional BEST1 variant in a patient with autosomal recessive bestrophinopathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Luo et al., 2019); This variant is associated with the following publications: (PMID: 28687848, 29555955, 21878505, 23825107, 25489231, 29668979, 9700209, 30593719, 31570112, 31519547, 32239196, 29288639, 23213274, 29781975, 22633354) -

Vitelliform macular dystrophy 2 Pathogenic:2

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + (PM5, p.Arg218Leu; p.Arg218Gly; p.Arg218His). REVEL score is 0.9 (PP3_mod)). Prevalence in affected patients is greater compared to the general populace (PS4). + Experimental studies have shown that this missense change affects BEST1 function (PS3, PMID:15452084, 23825107). -

Retinal dystrophy Pathogenic:2

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vitelliform macular dystrophy 2;C2750789:Retinitis pigmentosa 50;C3888099:Autosomal dominant vitreoretinochoroidopathy;C3888198:Autosomal recessive bestrophinopathy Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.
PhyloP100		2.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.88
MutPred		0.99		Loss of disorder (P = 0.1578);.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281865238; hg19: chr11-61724874; COSMIC: COSV57121641; COSMIC: COSV57121641;