VCV000009474.53 - ClinVar

NM_001298.3(CNGA3):c.847C>T (p.Arg283Trp)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

11 out of 15 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001298.3(CNGA3):c.847C>T (p.Arg283Trp)

Variation ID: 9474 Accession: VCV000009474.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q11.2 2: 98396017 (GRCh38) [ NCBI UCSC ] 2: 99012480 (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	Jan 13, 2017	Mar 7, 2026	Oct 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001298.3:c.847C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001289.1:p.Arg283Trp	missense
NM_001079878.2:c.793C>T	NP_001073347.1:p.Arg265Trp	missense
NC_000002.12:g.98396017C>T
NC_000002.11:g.99012480C>T
NG_009097.1:g.54863C>T
	Q16281:p.Arg283Trp

... more HGVS ... less HGVS

Protein change

R283W, R265W

Other names

NP_001289.1:p.(Arg283Trp)

Canonical SPDI

NC_000002.12:98396016:C:T

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00010

Exome Aggregation Consortium (ExAC) 0.00014

Links

ClinGen: CA254820 UniProtKB: Q16281#VAR_010905 OMIM: 600053.0002 dbSNP: rs104893613 VarSome

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
Gene	OMIM	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	734	748

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.
Achromatopsia 2	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 4, 2024	RCV000010082.16
Monochromacy	Likely pathogenic (1)	criteria provided, single submitter	Jul 21, 2014	RCV000415133.3
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 7, 2024	RCV001222182.47
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 27, 2024	RCV004794328.3

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Jul 21, 2014) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Monochromacy	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492977.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Likely pathogenic (Sep 12, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Achromatopsia 2	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367338.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: show This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP3,PP5. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Nov 26, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001773382.3 First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023	Comment: show Published functional studies demonstrate a damaging effect consistent with loss-of-function (Muraki-Oda et al., 2007; Ding et al., 2010); 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: 26992781, 31237654, 32141364, 20238023, 24504161, 9662398, 16319819, 17693388, 11536077, 30682209, 31877759, 32869108, 33562422, 32037395) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Sep 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal recessive inheritance)	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905566.2 First in ClinVar: Sep 25, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Achromatopsia (present) Sex: male

Pathogenic (Oct 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV002063881.30 First in ClinVar: Jan 26, 2022 Last updated: Jan 11, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 4

Pathogenic (Mar 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001394271.7 First in ClinVar: Jul 16, 2020 Last updated: Mar 07, 2026	Publications: PubMed (7) PubMed: 11536077‚ 17693388‚ 20238023‚ 24504161‚ 25637600‚ 26992781‚ 9662398 Comment: show This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 283 of the CNGA3 protein (p.Arg283Trp). This variant is present in population databases (rs104893613, gnomAD 0.02%). This missense change has been observed in individual(s) with achromatopsia (PMID: 9662398, 11536077, 24504161, 25637600, 26992781). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9474). 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, 20238023). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jul 08, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Achromatopsia 2	Baylor Genetics Accession: SCV004041266.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jan 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinal dystrophy	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005071876.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (21) PubMed: 17693388‚ 20238023‚ 24504161‚ 26992781‚ 30682209‚ 31237654‚ 31429209‚ 31725702‚ 31877759‚ 31964843‚ 32037395‚ 32141364‚ 32531858‚ 32869108‚ 33562422‚ 34449556‚ 35456423‚ 36284460‚ 36460718‚ 36833446‚ 9662398 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Achromatopsia 2	Dubai Health Genomic Medicine Center, Dubai Health Accession: SCV005420630.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Comment: show PS3,PP1,PM3,PM2,PM5,PP3 (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Pathogenic (Apr 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Achromatopsia 2	Fulgent Genetics, Fulgent Genetics Accession: SCV005663329.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinal dystrophy	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV005415462.2 First in ClinVar: Nov 30, 2024 Last updated: Apr 13, 2025 Comment: This variant was classified as Pathogenic based on ACMG criteria: PS3_sup, PM1_mod, PM2_mod, PM5_mod, PP2_sup and PM3_very strong	Publications: PubMed (2) PubMed: 11536077‚ 9662398 Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Number of individuals with the variant: 3 Sex: male Geographic origin: Pakistan;Khyber Pakhtunkhwa

Pathogenic (Oct 01, 2001) N Not contributing to aggregate classification	no assertion criteria provided	ACHROMATOPSIA 2	OMIM Accession: SCV000030303.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017	Publications: PubMed (2) PubMed: 11536077‚ 9662398 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In affected members of a family with rod monochromacy (ACHM2; 216900), Kohl et al. (1998) found homozygosity for a C-to-T transition at nucleotide 887 of … (more) In affected members of a family with rod monochromacy (ACHM2; 216900), Kohl et al. (1998) found homozygosity for a C-to-T transition at nucleotide 887 of the CNGA3 gene, resulting in an arg283-to-trp (R283W) substitution. Wissinger et al. (2001) found the R283W mutation in 19 of 110 mutant alleles, including 14 alleles in 7 homozygous patients. Haplotype analysis suggested that these alleles, which were particularly frequent among patients from Scandinavia and northern Italy, have a common origin. Some of the patients homozygous for this mutation had complete achromatopsia with no detectable cone function, whereas others had incomplete achromatopsia with residual cone ERG responses and/or color vision. (less)

Pathogenic (Sep 01, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Achromatopsia 2	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804621.2 First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	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: SCV001956988.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	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: SCV001966736.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

Published functional studies demonstrate a damaging effect consistent with loss-of-function (Muraki-Oda et al., 2007; Ding et al., 2010); 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: 26992781, 31237654, 32141364, 20238023, 24504161, 9662398, 16319819, 17693388, 11536077, 30682209, 31877759, 32869108, 33562422, 32037395)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 283 of the CNGA3 protein (p.Arg283Trp). This variant is present in population databases (rs104893613, gnomAD 0.02%). This missense change has been observed in individual(s) with achromatopsia (PMID: 9662398, 11536077, 24504161, 25637600, 26992781). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9474). 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, 20238023). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and Genetic Features of Korean Patients with Achromatopsia.	Choi YJ	Genes	2023	PMID: 36833446
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.	Suga A	Human mutation	2022	PMID: 36284460
Delineating the Molecular and Phenotypic Spectrum of the CNGA3-Related Cone Photoreceptor Disorder in Pakistani Families.	Yousaf S	Genes	2022	PMID: 35456423
Disease Progression in CNGA3 and CNGB3 Retinopathy; Characteristics of Slovenian Cohort and Proposed OCT Staging Based on Pooled Data from 126 Patients from 7 Studies.	Tekavčič Pompe M	Current issues in molecular biology	2021	PMID: 34449556
Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study.	Brunetti-Pierri R	International journal of molecular sciences	2021	PMID: 33562422
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
Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period.	Weisschuh N	Human mutation	2020	PMID: 32531858
Genetic testing for inherited ocular conditions in a developing country.	Zanolli M	Ophthalmic genetics	2020	PMID: 32141364
Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32037395
Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.	Hanany M	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31964843
PHENOTYPE-GUIDED GENETIC TESTING OF PEDIATRIC INHERITED RETINAL DISEASE IN THE UNITED ARAB EMIRATES.	Khan AO	Retina (Philadelphia, Pa.)	2020	PMID: 31725702
Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge.	Holtan JP	Acta ophthalmologica	2020	PMID: 31429209
Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in ABCA4.	Rehman AU	Genes	2019	PMID: 31877759
Characterization of Retinal Structure in ATF6-Associated Achromatopsia.	Mastey RR	Investigative ophthalmology & visual science	2019	PMID: 31237654
Adaptive Optics Retinal Imaging in CNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability.	Georgiou M	Investigative ophthalmology & visual science	2019	PMID: 30682209
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
Novel CNGA3 mutations in Chinese patients with achromatopsia.	Liang X	The British journal of ophthalmology	2015	PMID: 25637600
Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia.	Greenberg JP	JAMA ophthalmology	2014	PMID: 24504161
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
Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel.	Kohl S	Nature genetics	1998	PMID: 9662398
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Text-mined citations for rs104893613 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026