ClinVar Genomic variation as it relates to human health
NM_004183.4(BEST1):c.728C>T (p.Ala243Val)
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.728C>T (p.Ala243Val)
Variation ID: 2737 Accession: VCV000002737.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.3 11: 61958159 (GRCh38) [ NCBI UCSC ] 11: 61725631 (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 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004183.4:c.728C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004174.1:p.Ala243Val missense NM_001139443.2:c.548C>T NP_001132915.1:p.Ala183Val missense NM_001300786.2:c.548C>T NP_001287715.1:p.Ala183Val missense NM_001300787.2:c.548C>T NP_001287716.1:p.Ala183Val missense NM_001363591.2:c.410C>T NP_001350520.1:p.Ala137Val missense NM_001363592.1:c.728C>T NP_001350521.1:p.Ala243Val missense NM_001363593.2:c.-448C>T 5 prime UTR NR_134580.2:n.841C>T non-coding transcript variant NC_000011.10:g.61958159C>T NC_000011.9:g.61725631C>T NG_009033.1:g.13276C>T O76090:p.Ala243Val - Protein change
- A243V, A183V, A137V
- Other names
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- Canonical SPDI
- NC_000011.10:61958158: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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 |
818 | 885 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 3, 2022 | RCV000002858.9 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV000086167.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 11, 2019 | RCV001075633.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2023 | RCV003326112.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV003448243.1 |
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
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446682.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Macular degeneration (present)
Sex: female
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 2
Affected status: yes
Allele origin:
unknown
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548129.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Likely pathogenic
(Mar 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581427.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_MOD, PP1_MOD, PM2_SUP, PP3
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Number of individuals with the variant: 4
Sex: female
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Pathogenic
(Jan 23, 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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Invitae
Accession: SCV001212418.5
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 243 of the BEST1 protein (p.Ala243Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 243 of the BEST1 protein (p.Ala243Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant macular dystrophy (PMID: 10854112, 28225368, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2737). 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: 17065513, 24560797). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2024)
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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: SCV001245802.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
BEST1: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 8
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Pathogenic
(Feb 04, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000704550.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Feb 11, 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: SCV001241260.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Aug 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant vitreoretinochoroidopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004032306.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PM5_STR,PS3_MOD,PS4_MOD,PM1,PM2_SUP,PP3
Clinical Features:
Obesity (present) , Mild global developmental delay (present) , Hypotonia (present) , Hypermetropia (present) , Spastic hemiparesis (present)
Sex: female
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004175991.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
Criteria applied: PS4,PM5_STR,PS3_MOD,PM1,PM2_SUP
Clinical Features:
Macular dystrophy (present) , Vitelliform-like macular lesions (present)
Sex: male
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Pathogenic
(Apr 01, 2000)
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no assertion criteria provided
Method: literature only
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MACULAR DYSTROPHY, VITELLIFORM, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023016.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 02, 2015 |
Comment on evidence:
In 8 unrelated patients with vitelliform macular dystrophy (VMD2; 153700), 3 with onset of disease in childhood and 5 with onset in adulthood, Kramer et … (more)
In 8 unrelated patients with vitelliform macular dystrophy (VMD2; 153700), 3 with onset of disease in childhood and 5 with onset in adulthood, Kramer et al. (2000) identified heterozygosity for a 728C-T transition in exon 7 of the BEST1 gene, resulting in an ala243-to-val (A243V) substitution. Four of the patients, 3 with childhood-onset disease and 1 with adult-onset, had a first-degree affected relative who also carried the mutation. (less)
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Likely pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Vitelliform macular dystrophy type 2
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926520.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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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: SCV000118311.1
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.728C>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 |
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION. | Khan KN | Retina (Philadelphia, Pa.) | 2018 | PMID: 28225368 |
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
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 |
BEST1 sequence variants in Italian patients with vitelliform macular dystrophy. | Sodi A | Molecular vision | 2012 | PMID: 23213274 |
The spectrum of subclinical Best vitelliform macular dystrophy in subjects with mutations in BEST1 gene. | Querques G | Investigative ophthalmology & visual science | 2011 | PMID: 21436265 |
Fundus autofluorescence imaging of retinal dystrophies. | Boon CJ | Vision research | 2008 | PMID: 18289629 |
Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration. | Krämer F | European journal of human genetics : EJHG | 2000 | PMID: 10854112 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BEST1 | - | - | - | - |
Text-mined citations for rs28940570 ...
HelpRecord last updated May 19, 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.