ClinVar Genomic variation as it relates to human health
NM_019098.5(CNGB3):c.1208G>A (p.Arg403Gln)
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(2); Uncertain significance(1); Benign(3); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_019098.5(CNGB3):c.1208G>A (p.Arg403Gln)
Variation ID: 143154 Accession: VCV000143154.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.3 8: 86632864 (GRCh38) [ NCBI UCSC ] 8: 87645092 (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 Aug 10, 2014 May 12, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_019098.5:c.1208G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061971.3:p.Arg403Gln missense NC_000008.11:g.86632864C>T NC_000008.10:g.87645092C>T NG_016980.1:g.115812G>A Q9NQW8:p.Arg403Gln - Protein change
- R403Q
- Other names
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- Canonical SPDI
- NC_000008.11:86632863: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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0.00699 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00119
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00138
Trans-Omics for Precision Medicine (TOPMed) 0.00141
The Genome Aggregation Database (gnomAD), exomes 0.00458
Exome Aggregation Consortium (ExAC) 0.00511
1000 Genomes Project 0.00699
1000 Genomes Project 30x 0.00781
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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CNGB3 | - | - |
GRCh38 GRCh37 |
1220 | 1264 |
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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Benign (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000132679.16 | |
Likely benign (2) |
criteria provided, single submitter
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May 18, 2021 | RCV000174144.5 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 7, 2023 | RCV000435881.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2017 | RCV000501136.5 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2016 | RCV000678546.3 | |
Pathogenic (3) |
criteria provided, single submitter
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Mar 20, 2018 | RCV000597492.4 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV001164460.7 |
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
(Jun 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Disorder of eye
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000588362.2
First in ClinVar: Aug 28, 2017 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 20-29 years
Sex: female
Ethnicity/Population group: Persian
Geographic origin: Iran
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Benign
(May 27, 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: SCV000512655.5
First in ClinVar: Mar 08, 2017 Last updated: May 06, 2023 |
Comment:
See Variant Classification Assertion Criteria.
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Benign
(Jan 31, 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: SCV001105918.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Pathogenic
(Mar 20, 2018)
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criteria provided, single submitter
Method: research
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Achromatopsia
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, Institute for Ophthalmic Research
Accession: SCV000700212.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
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Likely benign
(Apr 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000225390.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001326587.1
First in ClinVar: May 31, 2020 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(-)
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criteria provided, single submitter
Method: research
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Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435146.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The p.Arg403Gln variant in CNGB3 has been identified in 3 homozygous Pakistani individuals with progressive cone dystrophy, 1 homozygous Pakistani individual with complete achromatopsia, and … (more)
The p.Arg403Gln variant in CNGB3 has been identified in 3 homozygous Pakistani individuals with progressive cone dystrophy, 1 homozygous Pakistani individual with complete achromatopsia, and in the heterozygous state in 1 individual with progressive cone dystrophy, segregated with eye disease in 4 relatives from 1 family (PMID: 15161866, 24504161), and has been identified in >2% of South Asian chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg403Gln variant may slightly impact protein function (PMID: 16379026). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive progressive cone dystrophy. (less)
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Likely benign
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia 3
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001737262.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
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Uncertain significance
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844722.2
First in ClinVar: Mar 26, 2023 Last updated: Feb 04, 2024 |
Comment:
Variant summary: CNGB3 c.1208G>A (p.Arg403Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four … (more)
Variant summary: CNGB3 c.1208G>A (p.Arg403Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251014 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 24 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Biallelic mutations in CNBG3 cause autosomal recessive Achromatopsia. However, the c.1208G>A variant has been reported in patients who present with a highly variable range of clinical findings from mild macular dystrophy to severe cone dystrophy with near complete loss of cone function (eg. Michaelides_2004, Lin_2017, Greenberg_2014, Jinda_2021, Burkard_2018, Mayer_2017). One in depth exploration of a large cohort of patients with the variant suggests the variant is a hypomorphic mutation that may cause relatively mild and late-onset or subclinical retinal disease in the homozygous state and may be a cause of digenic triallelic disease due to the correlation of disease severity with CNGB3 and CNGA3 genoytpes (Burkard_2018). Consistent with the clinical findings, a Cngb3-R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3/) mice to obtain triallelic Cnga3+/ Cngb3R403Q/R403Q mutants showed striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice (Burkard_2018). A different functional study found that co-expression of WT CNGA3 and mutant CNGB3/p.R403Q in Xenopus oocytes resulted in formation of heterotetrameric CNG channels with normal surface expression, but increased apparent ligand sensitivity and increased outward rectification, suggesting a gain-of-function mechanism (Bright_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16379026, 30418171, 24504161, 32869108, 28418496, 28795510, 15161866). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Six submitters classified the variant as benign/likely benign, four classified the variant as pathogenic/likely pathogenic, and two classified it as VUS. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance. (less)
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Benign
(Jan 01, 2023)
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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: SCV003917614.8
First in ClinVar: Apr 23, 2023 Last updated: May 12, 2024 |
Comment:
CNGB3: BS1, BS2
Number of individuals with the variant: 1
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probable-non-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Department of Ophthalmology and Visual Sciences Kyoto University
Accession: SCV000172631.1
First in ClinVar: Aug 10, 2014 Last updated: Aug 10, 2014 |
Comment:
Converted during submission to Likely benign.
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Likely pathogenic
(Mar 27, 2017)
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no assertion criteria provided
Method: research
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ACHM3
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, Institute for Ophthalmic Research
Accession: SCV000575809.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Uncertain significance
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804624.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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achromatopsia
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161027.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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Uncertain significance
(Jan 08, 2020)
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no assertion criteria provided
Method: clinical testing
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Achromatopsia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455000.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Molecular and clinical characterization of Thai patients with achromatopsia: identification of three novel disease-associated variants in the CNGA3 and CNGB3 genes. | Jinda W | International ophthalmology | 2021 | PMID: 32869108 |
Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. | Burkard M | The Journal of clinical investigation | 2018 | PMID: 30418171 |
CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. | Mayer AK | Human mutation | 2017 | PMID: 28795510 |
Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families. | Li L | Investigative ophthalmology & visual science | 2017 | PMID: 28418496 |
Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia. | Greenberg JP | JAMA ophthalmology | 2014 | PMID: 24504161 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels. | Bright SR | Molecular vision | 2005 | PMID: 16379026 |
Progressive cone dystrophy associated with mutation in CNGB3. | Michaelides M | Investigative ophthalmology & visual science | 2004 | PMID: 15161866 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CNGB3 | - | - | - | - |
Text-mined citations for rs147876778 ...
HelpRecord last updated May 12, 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.