ClinVar Genomic variation as it relates to human health
NM_001298.3(CNGA3):c.1306C>T (p.Arg436Trp)
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
-
NM_001298.3(CNGA3):c.1306C>T (p.Arg436Trp)
Variation ID: 9482 Accession: VCV000009482.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q11.2 2: 98396476 (GRCh38) [ NCBI UCSC ] 2: 99012939 (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 Apr 21, 2017 May 12, 2024 Jan 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001298.3:c.1306C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001289.1:p.Arg436Trp missense NM_001079878.2:c.1252C>T NP_001073347.1:p.Arg418Trp missense NC_000002.12:g.98396476C>T NC_000002.11:g.99012939C>T NG_009097.1:g.55322C>T Q16281:p.Arg436Trp - Protein change
- R436W, R418W
- Other names
- -
- Canonical SPDI
- NC_000002.12:98396475:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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. |
|||
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. |
---|---|---|---|---|
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Aug 26, 2022 | RCV000010090.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 20, 2018 | RCV000591222.8 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV001042434.31 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 13, 2018 | RCV001075358.5 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Mar 20, 2018)
|
criteria provided, single submitter
Method: research
|
Achromatopsia
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, Institute for Ophthalmic Research
Accession: SCV000700224.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
|
|
Pathogenic
(Mar 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Achromatopsia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712807.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
The p.Arg436Trp (NM001298.2 c.1306C>T) variant in CNGA3 has been reported in at least 2 homozygous and 10 compound heterozygous individuals with clinical diagno sis of … (more)
The p.Arg436Trp (NM001298.2 c.1306C>T) variant in CNGA3 has been reported in at least 2 homozygous and 10 compound heterozygous individuals with clinical diagno sis of achromatopsia or cone-rod dystrophy (Li 2014, Wissinger 2001, Johnson 200 4, Goto-Omoto 2006, Saqib 2015, Huang 2016, Nishiguchi 2005, Zelinger 2015, and Genead 2011), and segregated in 3 affected homozygous family members in one fami ly (Saqib 2015). This variant has also been identified in 0.036% (6/16,458) of S outh Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs104893621). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessi ve carrier frequency. In summary, this variant meets criteria to be classified a s pathogenic for CNGA3-related achromatopsia/ cone-rod dystrophy in an autosomal recessive manner based upon its biallelic occurrence in affected individuals an d low frequency in control populations. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Achromatopsia type 2
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424393.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
|
|
Pathogenic
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249387.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
CNGA3: PM3:Very Strong, PM1, PM2, PS3:Supporting
Number of individuals with the variant: 4
|
|
Pathogenic
(May 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001240979.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
Pathogenic
(Aug 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Achromatopsia 2
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572355.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: CNGA3 c.1306C>T (p.Arg436Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CNGA3 c.1306C>T (p.Arg436Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250684 control chromosomes. c.1306C>T has been reported in the literature in multiple individuals affected with Achromatopsia and has been shown to segregate in families (eg. Saqib_2015, Wissinger_2001, etc). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown the variant to have absent cGMP-activated current upon patch-clamp recordings, suggesting that this mutation causes a loss of function of the channels (Muraki-Oda_2007). Additionally, a mouse model demonstrated the variant to result in a loss of activity and impaired cellular trafficking, as a result of changes to the secondary structure (Matveev_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Oct 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001801175.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with loss of activity and impaired cellular trafficking, as a result of changes to the secondary structure (Muraki-Oda … (more)
Published functional studies demonstrate a damaging effect with loss of activity and impaired cellular trafficking, as a result of changes to the secondary structure (Muraki-Oda et al., 2007; Matveev et al., 2010); This variant is associated with the following publications: (PMID: 16961972, 32531858, 26992781, 20088482, 11536077, 25943428, 25616768, 21778272, 15712225, 14757870, 17693388, 30804581, 30609409, 30682209, 24903488, 30418171, 31456290, 33083013, 34426522) (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Achromatopsia 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV004037132.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Achromatopsia 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100367.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.R436W in CNGA3 (NM_001298.3) has been previously reported in multiple affected individuals (Li S et al,Huang L et al). Functional studies suggest … (more)
The missense variant p.R436W in CNGA3 (NM_001298.3) has been previously reported in multiple affected individuals (Li S et al,Huang L et al). Functional studies suggest a damaging effect (Muraki-Oda S et al). In silico tools are damaging and the residue is poorly conserved across species. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Cone-rod dystrophy (present)
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001206113.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 436 of the CNGA3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 436 of the CNGA3 protein (p.Arg436Trp). This variant is present in population databases (rs104893621, gnomAD 0.04%). This missense change has been observed in individuals with retinal dystrophy (PMID: 11536077, 25943428, 26992781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9482). 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: 17693388). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 01, 2001)
|
no assertion criteria provided
Method: literature only
|
ACHROMATOPSIA 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030311.3
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 1306 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 1306 of the CNGA3 gene, resulting in an arg436-to-trp (R436W) substitution; the mutation was found in 6 of 110 mutant alleles. All but 1 of the patients with this mutation were of German origin. Haplotype analysis suggested multiple origins of the mutation. (less)
|
|
Likely pathogenic
(Jun 23, 2019)
|
no assertion criteria provided
Method: research
|
achromatopsia
Affected status: yes
Allele origin:
inherited
|
Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161015.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Achromatopsia 2
Affected status: yes
Allele origin:
inherited
|
Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001450753.1
First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020 |
Number of individuals with the variant: 2
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001955901.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969512.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
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 |
Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies. | Saqib MA | Scientific reports | 2015 | PMID: 25943428 |
Genetics and Disease Expression in the CNGA3 Form of Achromatopsia: Steps on the Path to Gene Therapy. | Zelinger L | Ophthalmology | 2015 | PMID: 25616768 |
Identification of CNGA3 mutations in 46 families: common cause of achromatopsia and cone-rod dystrophies in Chinese patients. | Li S | JAMA ophthalmology | 2014 | PMID: 24903488 |
Photoreceptor structure and function in patients with congenital achromatopsia. | Genead MA | Investigative ophthalmology & visual science | 2011 | PMID: 21778272 |
The disease-causing mutations in the carboxyl terminus of the cone cyclic nucleotide-gated channel CNGA3 subunit alter the local secondary structure and interfere with the channel active conformational change. | Matveev AV | Biochemistry | 2010 | PMID: 20088482 |
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 |
Compound heterozygous CNGA3 mutations (R436W, L633P) in a Japanese patient with congenital achromatopsia. | Goto-Omoto S | Visual neuroscience | 2006 | PMID: 16961972 |
Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. | Nishiguchi KM | Human mutation | 2005 | PMID: 15712225 |
Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. | Johnson S | Journal of medical genetics | 2004 | PMID: 14757870 |
CNGA3 mutations in hereditary cone photoreceptor disorders. | Wissinger B | American journal of human genetics | 2001 | PMID: 11536077 |
click to load more click to collapse |
Text-mined citations for rs104893621 ...
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.