ClinVar Genomic variation as it relates to human health
NM_001298.3(CNGA3):c.1279C>T (p.Arg427Cys)
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.1279C>T (p.Arg427Cys)
Variation ID: 497256 Accession: VCV000497256.62
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q11.2 2: 98396449 (GRCh38) [ NCBI UCSC ] 2: 99012912 (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 2, 2018 May 12, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001298.3:c.1279C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001289.1:p.Arg427Cys missense NM_001079878.2:c.1225C>T NP_001073347.1:p.Arg409Cys missense NC_000002.12:g.98396449C>T NC_000002.11:g.99012912C>T NG_009097.1:g.55295C>T - Protein change
- R427C, R409C
- Other names
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- Canonical SPDI
- NC_000002.12:98396448: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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0.00040 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00035
The Genome Aggregation Database (gnomAD) 0.00036
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00040
1000 Genomes Project 30x 0.00047
Exome Aggregation Consortium (ExAC) 0.00049
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
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
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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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CNGA3 | - | - |
GRCh38 GRCh37 |
701 | 720 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000596729.28 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2016 | RCV000678541.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV000596662.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 31, 2022 | RCV001196267.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2018 | RCV001075180.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814192.2 |
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
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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
(Nov 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: SCV001249386.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 28, 2016)
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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: SCV000701669.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(Sep 12, 2019)
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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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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366833.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
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Pathogenic
(Jan 22, 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: SCV001389552.5
First in ClinVar: Jul 16, 2020 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 427 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 427 of the CNGA3 protein (p.Arg427Cys). This variant is present in population databases (rs141386891, gnomAD 0.2%). This missense change has been observed in individual(s) with achromatopsia or cone dystrophy (PMID: 11536077, 18445228, 23972307, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 497256). 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: 18445228). For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV000700223.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the eye
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755240.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(May 24, 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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GeneDx
Accession: SCV001802563.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Published functional studies of this variant demonstrates that cGMP maximum currents of mutant channels were reduced, and the chemical chaperone glycerol significantly enhanced surface expression … (more)
Published functional studies of this variant demonstrates that cGMP maximum currents of mutant channels were reduced, and the chemical chaperone glycerol significantly enhanced surface expression of mutant channels and macroscopic currents, which may indicate impaired folding and trafficking of the mutant channel protein (Koeppen et al., 2008); 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: 31290651, 30418171, 30653986, 28559085, 30682209, 28341476, 23362848, 24148654, 18445228, 23972307, 24269407, 17652762, 11536077, 15712225, 17693388, 16961972, 19874885, 3039450) (less)
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Pathogenic
(Jul 17, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002017391.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966883.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Arg427Cys variant in CNGA3 has been reported in 9 compound heterozygous in dividuals with clinical diagnosis of achromatopsia or cone-rod dystrophy (Wissin ger 2001, … (more)
The p.Arg427Cys variant in CNGA3 has been reported in 9 compound heterozygous in dividuals with clinical diagnosis of achromatopsia or cone-rod dystrophy (Wissin ger 2001, Koeppen 2008, Fahim 2013, Taylor 2017), and segregated in 2 affected f amily members (Koeppen 2008, Fahim 2013). This variant has also been identified in 0.15% (47/30754) of South Asian chromosomes, including 1 homozygote, by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs1 41386891). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In vi tro functional studies provide some evidence that the p.Arg427Cys variant may im pact protein function, resulting in a decreased channel density in the cell memb rane (Koeppen 2008, Muraki-Oda 2007). In summary, this variant is pathogenic for achromatopsia in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_ VeryStrong; PS3_Moderate; PP3; PP1. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766657.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with achromatopsia 2 (MIM#216900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been described within sibling pairs (PMID: 30682209). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (108 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg427Leu)) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and observed in compound heterozygous individuals with achromatopsia and retinal dystrophy (ClinVar, LOVD, PMID: 30653986). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Nov 02, 2018)
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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: SCV001240792.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Achromatopsia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004100328.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Clinical Features:
Cone-rod dystrophy (present) , Progressive cone degeneration (present)
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Uncertain significance
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Macular dystrophy
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804618.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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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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Adaptive Optics Retinal Imaging in CNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability. | Georgiou M | Investigative ophthalmology & visual science | 2019 | PMID: 30682209 |
The Oculome Panel Test: Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders. | Patel A | Ophthalmology | 2019 | PMID: 30653986 |
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. | Taylor RL | Ophthalmology | 2017 | PMID: 28341476 |
Diagnostic fundus autofluorescence patterns in achromatopsia. | Fahim AT | American journal of ophthalmology | 2013 | PMID: 23972307 |
Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). | Koeppen K | The European journal of neuroscience | 2008 | PMID: 18445228 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CNGA3 | - | - | - | - |
Text-mined citations for rs141386891 ...
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.