ClinVar Genomic variation as it relates to human health
NM_004183.4(BEST1):c.602T>C (p.Ile201Thr)
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.
Pathogenic(3); Likely pathogenic(3); Uncertain significance(1); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004183.4(BEST1):c.602T>C (p.Ile201Thr)
Variation ID: 99726 Accession: VCV000099726.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.3 11: 61956964 (GRCh38) [ NCBI UCSC ] 11: 61724436 (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 Apr 15, 2024 Nov 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004183.4:c.602T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004174.1:p.Ile201Thr missense NM_001139443.2:c.422T>C NP_001132915.1:p.Ile141Thr missense NM_001300786.2:c.422T>C NP_001287715.1:p.Ile141Thr missense NM_001300787.2:c.422T>C NP_001287716.1:p.Ile141Thr missense NM_001363591.2:c.284T>C NP_001350520.1:p.Ile95Thr missense NM_001363592.1:c.602T>C NP_001350521.1:p.Ile201Thr missense NM_001363593.2:c.-574T>C 5 prime UTR NR_134580.2:n.715T>C non-coding transcript variant NC_000011.10:g.61956964T>C NC_000011.9:g.61724436T>C NG_009033.1:g.12081T>C O76090:p.Ile201Thr - Protein change
- I201T, I141T, I95T
- Other names
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- Canonical SPDI
- NC_000011.10:61956963:T:C
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00007
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 |
816 | 883 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV000086141.18 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2020 | RCV000169651.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000312619.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000344091.6 | |
Benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000408002.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 8, 2021 | RCV001376213.2 |
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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Likely pathogenic
(Sep 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive bestrophinopathy
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000221175.3
First in ClinVar: Apr 01, 2015 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 2
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Pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Vitelliform macular dystrophy 2
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573277.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 13, 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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Invitae
Accession: SCV002239752.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Apr 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive bestrophinopathy
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503699.2
First in ClinVar: Apr 23, 2022 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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BEST1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000372735.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
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Benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant vitreoretinochoroidopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000372734.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000372733.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely pathogenic
(Mar 01, 2021)
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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: SCV001746996.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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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: SCV000118285.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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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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Patient-specific mutations impair BESTROPHIN1's essential role in mediating Ca(2+)-dependent Cl(-) currents in human RPE. | Li Y | eLife | 2017 | PMID: 29063836 |
FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY. | Khan KN | Retina (Philadelphia, Pa.) | 2017 | PMID: 27764019 |
Biallelic Mutations in the BEST1 Gene: Additional Families with Autosomal Recessive Bestrophinopathy. | Wivestad Jansson R | Ophthalmic genetics | 2016 | PMID: 26333019 |
A novel compound heterozygous mutation in the BEST1 gene causes autosomal recessive Best vitelliform macular dystrophy. | Zhao L | Eye (London, England) | 2012 | PMID: 22422030 |
Modeling the structural consequences of BEST1 missense mutations. | Guziewicz KE | Advances in experimental medicine and biology | 2012 | PMID: 22183385 |
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 |
Best's macular dystrophy in Australia: phenotypic profile and identification of novel BEST1 mutations. | Cohn AC | Eye (London, England) | 2011 | PMID: 21109774 |
Insertion and topology of normal and mutant bestrophin-1 in the endoplasmic reticulum membrane. | Milenkovic VM | The Journal of biological chemistry | 2007 | PMID: 17110374 |
Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. | Lotery AJ | Investigative ophthalmology & visual science | 2000 | PMID: 10798642 |
Text-mined citations for rs199529046 ...
HelpRecord last updated Apr 15, 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.