This individual is homozygous for the c.400C>G variant in the BEST1 gene, which results in the amino acid substitution of leucine to valine at residue 134, p.(Leu134Val). This variant has been reported in the gnomAD v2.1.1 browser (http://gnomad.broadinstitute.org accessed: 28/03/2022) with a very low allele frequency of 0.003% (5 out of 150,438 alleles). All five individuals in gnomAD are heterozygous for the variant, there are no individuals in gnomAD that are homozygous for this variant. This variant has been previously reported in multiple individuals with autosomal recessive bestrophinopathy as either a homozygous variant or in compound heterozygosity with other disease-causing BEST1 variants (Nowomiejska et al 2021 PMID: 34327816; Hufendiek et al 2020 PMID: 33302512; Shah et al 2020 PMID: 32239196; Deak et al 2019 PMID: 29215532; Guziewicz et al 2018 PMID: 29507198). In silico analysis of pathogenicity (through Alamut Visual v2.13) using PolyPhen2, SIFT and MutationTaster is inconclusive regarding this change; PolyPhen2 and MutationTaster predict the variant to be deleterious to the protein, whereas SIFT predicts the variant to be tolerated. This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM2, PM3_strong, PP4).
ClinVar Genomic variation as it relates to human health
NM_004183.4(BEST1):c.400C>G (p.Leu134Val)
Germline
Classification
Help
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.
(4)
Help
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/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004183.4(BEST1):c.400C>G (p.Leu134Val)
Variation ID: 427886 Accession: VCV000427886.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q12.3 11: 61955870 (GRCh38) [ NCBI UCSC ] 11: 61723342 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 25, 2017 Oct 20, 2024 Aug 10, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004183.4:c.400C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004174.1:p.Leu134Val missense NM_001139443.2:c.220C>G NP_001132915.1:p.Leu74Val missense NM_001300786.2:c.220C>G NP_001287715.1:p.Leu74Val missense NM_001300787.2:c.220C>G NP_001287716.1:p.Leu74Val missense NM_001363591.2:c.82C>G NP_001350520.1:p.Leu28Val missense NM_001363592.1:c.400C>G NP_001350521.1:p.Leu134Val missense NM_001363593.2:c.-776C>G 5 prime UTR NR_134580.2:n.513C>G non-coding transcript variant NC_000011.10:g.61955870C>G NC_000011.9:g.61723342C>G NG_009033.1:c.400C>G NG_009033.1:g.10987C>G - Protein change
- L134V, L28V, L74V
- Other names
- -
- Canonical SPDI
- NC_000011.10:61955869:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
protein truncation; Variation Ontology [ VariO:0015]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| BEST1 | - | - |
GRCh38 GRCh37 |
831 | 903 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
Mar 28, 2022 | RCV000491340.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 10, 2023 | RCV001060439.34 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive bestrophinopathy
Affected status: unknown
Allele origin:
germline
|
Sydney Genome Diagnostics, Children's Hospital Westmead
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002549761.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
Comment:
This individual is homozygous for the c.400C>G variant in the BEST1 gene, which results in the amino acid substitution of leucine to valine at residue … (more)
This individual is homozygous for the c.400C>G variant in the BEST1 gene, which results in the amino acid substitution of leucine to valine at residue 134, p.(Leu134Val). This variant has been reported in the gnomAD v2.1.1 browser (http://gnomad.broadinstitute.org accessed: 28/03/2022) with a very low allele frequency of 0.003% (5 out of 150,438 alleles). All five individuals in gnomAD are heterozygous for the variant, there are no individuals in gnomAD that are homozygous for this variant. This variant has been previously reported in multiple individuals with autosomal recessive bestrophinopathy as either a homozygous variant or in compound heterozygosity with other disease-causing BEST1 variants (Nowomiejska et al 2021 PMID: 34327816; Hufendiek et al 2020 PMID: 33302512; Shah et al 2020 PMID: 32239196; Deak et al 2019 PMID: 29215532; Guziewicz et al 2018 PMID: 29507198). In silico analysis of pathogenicity (through Alamut Visual v2.13) using PolyPhen2, SIFT and MutationTaster is inconclusive regarding this change; PolyPhen2 and MutationTaster predict the variant to be deleterious to the protein, whereas SIFT predicts the variant to be tolerated. This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM2, PM3_strong, PP4). (less)
|
|
|
Pathogenic
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001225126.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 427886). This missense change has been observed in individuals with autosomal recessive bestrophinopathy (PMID: 29507198, 32239196, 33302512). This variant has been reported in individual(s) with autosomal dominant Best vitelliform macular dystrophy (PMID: 17287362); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs753614067, gnomAD 0.008%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the BEST1 protein (p.Leu134Val). (less)
|
|
|
Pathogenic
(Jul 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245798.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 25, 2015)
|
no assertion criteria provided
Method: research
|
Autosomal recessive bestrophinopathy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Laboratorio de Imunogenetica e Histocompatibilidade, Universidade Federal do Parana
Accession: SCV000502995.1
First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017 |
Comment:
The variant c.400C>G together with c.422G>A believed be causative of Bestrophinopathy autossomic recessive (BAR). It was first related of this combination of the two variants … (more)
The variant c.400C>G together with c.422G>A believed be causative of Bestrophinopathy autossomic recessive (BAR). It was first related of this combination of the two variants related to BAR. (less)
Clinical Features:
Reduced visual acuity (present) , Decreased light- and dark-adapted electroretinogram amplitude (present)
Age: 20-29 years
Sex: female
Ethnicity/Population group: Europe
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 427886). This missense change has been observed in individuals with autosomal recessive bestrophinopathy (PMID: 29507198, 32239196, 33302512). This variant has been reported in individual(s) with autosomal dominant Best vitelliform macular dystrophy (PMID: 17287362); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs753614067, gnomAD 0.008%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the BEST1 protein (p.Leu134Val).
Comment:
The variant c.400C>G together with c.422G>A believed be causative of Bestrophinopathy autossomic recessive (BAR). It was first related of this combination of the two variants related to BAR.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
protein truncation
|
|
|
Laboratorio de Imunogenetica e Histocompatibilidade, Universidade Federal do Parana
Accession: SCV000502995.1
|
|
Comment:
This individual is homozygous for the c.400C>G variant in the BEST1 gene, which results in the amino acid substitution of leucine to valine at residue 134, p.(Leu134Val). This variant has been reported in the gnomAD v2.1.1 browser (http://gnomad.broadinstitute.org accessed: 28/03/2022) with a very low allele frequency of 0.003% (5 out of 150,438 alleles). All five individuals in gnomAD are heterozygous for the variant, there are no individuals in gnomAD that are homozygous for this variant. This variant has been previously reported in multiple individuals with autosomal recessive bestrophinopathy as either a homozygous variant or in compound heterozygosity with other disease-causing BEST1 variants (Nowomiejska et al 2021 PMID: 34327816; Hufendiek et al 2020 PMID: 33302512; Shah et al 2020 PMID: 32239196; Deak et al 2019 PMID: 29215532; Guziewicz et al 2018 PMID: 29507198). In silico analysis of pathogenicity (through Alamut Visual v2.13) using PolyPhen2, SIFT and MutationTaster is inconclusive regarding this change; PolyPhen2 and MutationTaster predict the variant to be deleterious to the protein, whereas SIFT predicts the variant to be tolerated. This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM2, PM3_strong, PP4).
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 427886). This missense change has been observed in individuals with autosomal recessive bestrophinopathy (PMID: 29507198, 32239196, 33302512). This variant has been reported in individual(s) with autosomal dominant Best vitelliform macular dystrophy (PMID: 17287362); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs753614067, gnomAD 0.008%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the BEST1 protein (p.Leu134Val).
Comment:
The variant c.400C>G together with c.422G>A believed be causative of Bestrophinopathy autossomic recessive (BAR). It was first related of this combination of the two variants related to BAR.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies. | Nowomiejska K | Acta ophthalmologica | 2022 | PMID: 34327816 |
| Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene. | Hufendiek K | International journal of molecular sciences | 2020 | PMID: 33302512 |
| Association of Clinical and Genetic Heterogeneity With BEST1 Sequence Variations. | Shah M | JAMA ophthalmology | 2020 | PMID: 32239196 |
| IMAGING OF VITELLIFORM MACULAR LESIONS USING POLARIZATION-SENSITIVE OPTICAL COHERENCE TOMOGRAPHY. | Deák GG | Retina (Philadelphia, Pa.) | 2019 | PMID: 29215532 |
| BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. | Guziewicz KE | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 29507198 |
| New VMD2 gene mutations identified in patients affected by Best vitelliform macular dystrophy. | Marchant D | Journal of medical genetics | 2007 | PMID: 17287362 |
Text-mined citations for rs753614067 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.