ClinVar Genomic variation as it relates to human health
NM_004183.4(BEST1):c.584C>T (p.Ala195Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004183.4(BEST1):c.584C>T (p.Ala195Val)
Variation ID: 99725 Accession: VCV000099725.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.3 11: 61956946 (GRCh38) [ NCBI UCSC ] 11: 61724418 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Oct 20, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004183.4:c.584C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004174.1:p.Ala195Val missense NM_001139443.2:c.404C>T NP_001132915.1:p.Ala135Val missense NM_001300786.2:c.404C>T NP_001287715.1:p.Ala135Val missense NM_001300787.2:c.404C>T NP_001287716.1:p.Ala135Val missense NM_001363591.2:c.266C>T NP_001350520.1:p.Ala89Val missense NM_001363592.1:c.584C>T NP_001350521.1:p.Ala195Val missense NM_001363593.2:c.-592C>T 5 prime UTR NR_134580.2:n.697C>T non-coding transcript variant NC_000011.10:g.61956946C>T NC_000011.9:g.61724418C>T NG_009033.1:g.12063C>T O76090:p.Ala195Val - Protein change
- A195V, A135V, A89V
- Other names
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NM_001139443.1(BEST1):c.404C>T(p.Ala135Val)
NM_001300786.1(BEST1):c.404C>T(p.Ala135Val)
NM_001300787.1(BEST1):c.404C>T(p.Ala135Val)
NM_004183.3(BEST1):c.584C>T(p.Ala195Val)
- Canonical SPDI
- NC_000011.10:61956945:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00026
Trans-Omics for Precision Medicine (TOPMed) 0.00014
The Genome Aggregation Database (gnomAD) 0.00016
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BEST1 | - | - |
GRCh38 GRCh37 |
832 | 904 | |
FTH1 | - | - |
GRCh38 GRCh37 |
- | 91 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000086140.36 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2021 | RCV000490256.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV000678528.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2022 | RCV002477254.3 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2023 | RCV002247491.5 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 28, 2024 | RCV004732678.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001239946.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Jan 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000564700.6
First in ClinVar: Feb 20, 2014 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Likely pathogenic
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004025900.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Clinical Features:
Macular dystrophy (present)
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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Autosomal recessive bestrophinopathy
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267226.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely pathogenic
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Autosomal recessive bestrophinopathy
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803578.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 2
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518571.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Oct 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022041.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Dept Of Ophthalmology, Nagoya University
Accession: SCV004706983.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Pathogenic
(Nov 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive bestrophinopathy
Affected status: no
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503677.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive bestrophinopathy
Affected status: yes
Allele origin:
unknown
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548131.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Pathogenic
(Mar 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 2
Autosomal dominant vitreoretinochoroidopathy Autosomal recessive bestrophinopathy Retinitis pigmentosa 50
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002789856.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001217873.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245800.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804601.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 28, 2024)
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no assertion criteria provided
Method: clinical testing
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BEST1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005362167.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000118284.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_VMD2:c.584C>T
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
Novel BEST1 mutations and special clinical characteristics of autosomal recessive bestrophinopathy in Chinese patients. | Luo J | Acta ophthalmologica | 2019 | PMID: 30593719 |
Clinical and Mutation Analysis of Patients with Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy in Chinese Population. | Gao T | BioMed research international | 2018 | PMID: 30498755 |
BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes. | Milenkovic A | Human molecular genetics | 2018 | PMID: 29668979 |
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. | Birtel J | Scientific reports | 2018 | PMID: 29555955 |
Screening of BEST1 Gene in a Chinese Cohort With Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy. | Tian L | Investigative ophthalmology & visual science | 2017 | PMID: 28687848 |
A Novel BEST1 Mutation in Autosomal Recessive Bestrophinopathy. | Lee CS | Investigative ophthalmology & visual science | 2015 | PMID: 26720466 |
Mutation analysis of BEST1 in Japanese patients with Best's vitelliform macular dystrophy. | Katagiri S | The British journal of ophthalmology | 2015 | PMID: 26201355 |
Screening for BEST1 gene mutations in Chinese patients with bestrophinopathy. | Tian R | Molecular vision | 2014 | PMID: 25489231 |
Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1. | Johnson AA | Experimental eye research | 2014 | PMID: 24560797 |
Phenotype and genotype of patients with autosomal recessive bestrophinopathy. | MacDonald IM | Ophthalmic genetics | 2012 | PMID: 21809908 |
Childhood-onset autosomal recessive bestrophinopathy. | Borman AD | Archives of ophthalmology (Chicago, Ill. : 1960) | 2011 | PMID: 21825197 |
Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy. | Davidson AE | Investigative ophthalmology & visual science | 2011 | PMID: 21330666 |
Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients. | Kinnick TR | Retina (Philadelphia, Pa.) | 2011 | PMID: 21273940 |
VMD2 mutational analysis in a Japanese family with Best macular dystrophy. | Shiose S | Oman journal of ophthalmology | 2009 | PMID: 20927214 |
Detailed analysis of retinal function and morphology in a patient with autosomal recessive bestrophinopathy (ARB). | Gerth C | Documenta ophthalmologica. Advances in ophthalmology | 2009 | PMID: 18985398 |
Cortical image density determines the probability of target discovery during active search. | Motter BC | Vision research | 2000 | PMID: 10788642 |
Action of Legionella cytolysin on components of the phosphokinase system of eukaryotic cells. | Belyi YuF | Biomedical science | 1990 | PMID: 2133066 |
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Text-mined citations for rs200277476 ...
HelpRecord last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.