ClinVar Genomic variation as it relates to human health
NM_001298.3(CNGA3):c.682G>A (p.Glu228Lys)
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(1); Uncertain significance(3); Benign(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001298.3(CNGA3):c.682G>A (p.Glu228Lys)
Variation ID: 337659 Accession: VCV000337659.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q11.2 2: 98395852 (GRCh38) [ NCBI UCSC ] 2: 99012315 (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 Dec 6, 2016 Feb 20, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001298.3:c.682G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001289.1:p.Glu228Lys missense NM_001079878.2:c.628G>A NP_001073347.1:p.Glu210Lys missense NC_000002.12:g.98395852G>A NC_000002.11:g.99012315G>A NG_009097.1:g.54698G>A Q16281:p.Glu228Lys - Protein change
- E228K, E210K
- Other names
- -
- Canonical SPDI
- NC_000002.12:98395851:G:A
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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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0.00120 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
The Genome Aggregation Database (gnomAD) 0.00049
Trans-Omics for Precision Medicine (TOPMed) 0.00064
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00125
The Genome Aggregation Database (gnomAD), exomes 0.00137
Exome Aggregation Consortium (ExAC) 0.00155
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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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 (2) |
criteria provided, single submitter
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Mar 20, 2018 | RCV000273159.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV000778101.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 7, 2023 | RCV000733679.6 | |
Benign (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV001512908.6 |
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: SCV000700218.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 27, 2018)
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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: SCV000861772.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000432718.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The CNGA3 c.682G>A (p.Glu228Lys) variant was identified in a homozygous state in two siblings with achromatopsia (Reuter et al. 2008). A third individual was found … (more)
The CNGA3 c.682G>A (p.Glu228Lys) variant was identified in a homozygous state in two siblings with achromatopsia (Reuter et al. 2008). A third individual was found to carry the p.Glu228Lys variant in a compound heterozygous state with a second missense variant along with a homozygous missense variant in the CNGB3 gene (Thiadens et al. 2010). The p.Glu228Lys variant was absent from 100 controls and is reported at a frequency of 0.01005 in the South Asian population of the Exome Aggregation Consortium. Expression of wild type and p.Glu228Lys forms of the A3 channel in HEK293 cells revealed that p.Glu228Lys channels were localized intracellularly instead of at the cell membrane and showed decreased channel density compared to wild type. Based on the evidence, the p.Glu228Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: research
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Achromatopsia 2
(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: SCV001435234.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The homozygous p.Glu228Lys variant in CNGA3 has been identified in 2 siblings from 1 family with incomplete achromatopsia and in the heterozygous state in an … (more)
The homozygous p.Glu228Lys variant in CNGA3 has been identified in 2 siblings from 1 family with incomplete achromatopsia and in the heterozygous state in an individual with a different eye phenotype and other missense variants (PMID: 18521937, 20079539), and has been identified in >1% of South Asian chromosomes and a homozygote by ExAC (http://gnomad.broadinstitute.org/). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Glu228Lys variant may slightly impact protein function (PMID: 18521937). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(Jun 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: SCV004020821.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CNGA3 c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three … (more)
Variant summary: CNGA3 c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251304 control chromosomes in the gnomAD database, including 2 homozygotes. c.682G>A was found in homozygous state in two siblings with incomplete Achromatopsia (Reuter_ 2008), and in individuals affected with cone dystrophy (Thiadens _2010 and Hitti-malin_CNGA3_HM_2022). In at-least, one of these individuals affected with cone dystrophy authors reported a homozygous variant in CNGB3 (Thiadens _2010). These report(s) do not provide unequivocal conclusions about association of the variant with Achromatopsia 2. At least one publication reports experimental evidence evaluating an impact on protein function. However, it does not provide strong conclusions about the variant association with the disease (Reuter_ 2008). The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 30418171, 36259723, 27535533, 18521937, 26036949, 31456290, 32913385, 20079539). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2), pathogenic/likely pathogenic (n=2) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Benign
(Dec 31, 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: SCV001720408.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024 |
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Likely 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: SCV001161005.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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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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Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases. | Hitti-Malin RJ | Human mutation | 2022 | PMID: 36259723 |
Genotypes and phenotypes of genes associated with achromatopsia: A reference for clinical genetic testing. | Sun W | Molecular vision | 2020 | PMID: 32913385 |
A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC). | Sharon D | Human mutation | 2020 | PMID: 31456290 |
Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. | Burkard M | The Journal of clinical investigation | 2018 | PMID: 30418171 |
Analysis of protein-coding genetic variation in 60,706 humans. | Lek M | Nature | 2016 | PMID: 27535533 |
Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. | Shamseldin HE | Genome biology | 2015 | PMID: 26036949 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. | Thiadens AA | Ophthalmology | 2010 | PMID: 20079539 |
Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia. | Reuter P | Human mutation | 2008 | PMID: 18521937 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CNGA3 | - | - | - | - |
Text-mined citations for rs147415641 ...
HelpRecord last updated Mar 30, 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.