ClinVar Genomic variation as it relates to human health
NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys)
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_001298.3(CNGA3):c.829C>T (p.Arg277Cys)
Variation ID: 9481 Accession: VCV000009481.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q11.2 2: 98395999 (GRCh38) [ NCBI UCSC ] 2: 99012462 (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 Apr 21, 2017 May 12, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001298.3:c.829C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001289.1:p.Arg277Cys missense NM_001079878.2:c.775C>T NP_001073347.1:p.Arg259Cys missense NC_000002.12:g.98395999C>T NC_000002.11:g.99012462C>T NG_009097.1:g.54845C>T Q16281:p.Arg277Cys - Protein change
- R277C, R259C
- Other names
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- Canonical SPDI
- NC_000002.12:98395998: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD) 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
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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
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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CNGA3 | - | - |
GRCh38 GRCh37 |
701 | 720 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000010089.10 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV001092740.26 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 20, 2018 | RCV000596449.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626801.3 |
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
(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: SCV000700220.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
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Pathogenic
(Jul 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia 2
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001524042.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia 2
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518728.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(May 01, 2018)
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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: SCV001249382.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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Likely pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Color vision defect
Macular degeneration Photophobia
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747504.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Feb 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782956.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 14, 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: SCV001785648.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as R277C impaired channel activity compared to wild type CNGA3 (Muraki-Oda et al., 2007).; In silico analysis supports … (more)
Published functional studies demonstrate a damaging effect as R277C impaired channel activity compared to wild type CNGA3 (Muraki-Oda et al., 2007).; 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: 20238023, 21912902, 14736794, 14757870, 15712225, 16961972, 18521937, 15743887, 21911670, 26992781, 19592100, 24049715, 18445228, 23082193, 30682209, 30653986, 30418171, 31456290, 17693388, 11536077) (less)
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Pathogenic
(Dec 12, 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: SCV001591081.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 277 of the CNGA3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 277 of the CNGA3 protein (p.Arg277Cys). This variant is present in population databases (rs104893620, gnomAD 0.02%). This missense change has been observed in individuals with achromatopsia and cone dystrophy (PMID: 11536077). ClinVar contains an entry for this variant (Variation ID: 9481). 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 CNGA3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CNGA3 function (PMID: 20238023). This variant disrupts the p.Arg277 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11536077, 17693388, 26992781). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2001)
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no assertion criteria provided
Method: literature only
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ACHROMATOPSIA 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030310.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In patients with rod monochromacy (ACHM2; 216900), Wissinger et al. (2001) identified a C-to-T transition at nucleotide 829 of the CNGA3 gene, resulting in an … (more)
In patients with rod monochromacy (ACHM2; 216900), Wissinger et al. (2001) identified a C-to-T transition at nucleotide 829 of the CNGA3 gene, resulting in an arg277-to-cys (R277C) substitution; the mutation was found in 9 of 110 mutant alleles. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920829.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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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: SCV001161007.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959709.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 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 genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands. | Huang L | Experimental eye research | 2016 | PMID: 26992781 |
Molecular pathogenesis of achromatopsia associated with mutations in the cone cyclic nucleotide-gated channel CNGA3 subunit. | Ding XQ | Advances in experimental medicine and biology | 2010 | PMID: 20238023 |
Functional analysis of rod monochromacy-associated missense mutations in the CNGA3 subunit of the cone photoreceptor cGMP-gated channel. | Muraki-Oda S | Biochemical and biophysical research communications | 2007 | PMID: 17693388 |
CNGA3 mutations in hereditary cone photoreceptor disorders. | Wissinger B | American journal of human genetics | 2001 | PMID: 11536077 |
Text-mined citations for rs104893620 ...
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.