NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001092740.26

Allele description [Variation Report for NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys)]

NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys)

Gene:

CNGA3:cyclic nucleotide gated channel subunit alpha 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q11.2

Genomic location:

Preferred name:

NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys)

HGVS:

NC_000002.12:g.98395999C>T
NG_009097.1:g.54845C>T
NM_001079878.2:c.775C>T
NM_001298.3:c.829C>TMANE SELECT
NP_001073347.1:p.Arg259Cys
NP_001289.1:p.Arg277Cys
NP_001289.1:p.Arg277Cys
NC_000002.11:g.99012462C>T
NM_001298.2:c.829C>T
Q16281:p.Arg277Cys

Protein change:

R259C; ARG277CYS

Links:

UniProtKB: Q16281#VAR_047579; OMIM: 600053.0009; dbSNP: rs104893620

NCBI 1000 Genomes Browser:

rs104893620

Molecular consequence:

NM_001079878.2:c.775C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001298.3:c.829C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001249382	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2018)	germline	clinical testing	Citation Link,
SCV001591081	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20238023, 11536077, 17693388, 26992781, 28492532
SCV001785648	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 14, 2022)	germline	clinical testing	Citation Link,
SCV001920829	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001959709	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular pathogenesis of achromatopsia associated with mutations in the cone cyclic nucleotide-gated channel CNGA3 subunit.

Ding XQ, Fitzgerald JB, Quiambao AB, Harry CS, Malykhina AP.

Adv Exp Med Biol. 2010;664:245-53. doi: 10.1007/978-1-4419-1399-9_28.

PubMed [citation]

PMID:: 20238023
PMCID:: PMC3370940

CNGA3 mutations in hereditary cone photoreceptor disorders.

Wissinger B, Gamer D, Jägle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, et al.

Am J Hum Genet. 2001 Oct;69(4):722-37. Epub 2001 Aug 30.

PubMed [citation]

PMID:: 11536077
PMCID:: PMC1226059

See all PubMed Citations (5)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001249382.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Invitae, SCV001591081.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001785648.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001920829.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959709.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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