NM_001298.3(CNGA3):c.1279C>T (p.Arg427Cys) AND Achromatopsia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 31, 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:: RCV000596662.7

Allele description [Variation Report for NM_001298.3(CNGA3):c.1279C>T (p.Arg427Cys)]

NM_001298.3(CNGA3):c.1279C>T (p.Arg427Cys)

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.1279C>T (p.Arg427Cys)

HGVS:

NC_000002.12:g.98396449C>T
NG_009097.1:g.55295C>T
NM_001079878.2:c.1225C>T
NM_001298.3:c.1279C>TMANE SELECT
NP_001073347.1:p.Arg409Cys
NP_001289.1:p.Arg427Cys
NP_001289.1:p.Arg427Cys
NC_000002.11:g.99012912C>T
NM_001298.2:c.1279C>T
p.Arg427Cys

Protein change:

R409C

Links:

dbSNP: rs141386891

NCBI 1000 Genomes Browser:

rs141386891

Molecular consequence:

NM_001079878.2:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001298.3:c.1279C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Achromatopsia
Synonyms:: Rod monochromatism
Identifiers:: MONDO: MONDO:0018852; MedGen: C0152200; Human Phenotype Ontology: HP:0011516

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000700223	Molecular Genetics Laboratory, Institute for Ophthalmic Research	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000966883	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 5, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23972307, 17693388, 18445228, 11536077, 28341476, 24033266
SCV004100328	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000700223

Molecular Genetics Laboratory, Institute for Ophthalmic Research

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 20, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV000966883

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jun 5, 2018)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004100328

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnostic fundus autofluorescence patterns in achromatopsia.

Fahim AT, Khan NW, Zahid S, Schachar IH, Branham K, Kohl S, Wissinger B, Elner VM, Heckenlively JR, Jayasundera T.

Am J Ophthalmol. 2013 Dec;156(6):1211-1219.e2. doi: 10.1016/j.ajo.2013.06.033. Epub 2013 Aug 20.

PubMed [citation]

PMID:: 23972307

Functional analysis of rod monochromacy-associated missense mutations in the CNGA3 subunit of the cone photoreceptor cGMP-gated channel.

Muraki-Oda S, Toyoda F, Okada A, Tanabe S, Yamade S, Ueyama H, Matsuura H, Ohji M.

Biochem Biophys Res Commun. 2007 Oct 12;362(1):88-93. doi: 10.1016/j.bbrc.2007.07.152. Epub 2007 Aug 6.

PubMed [citation]

PMID:: 17693388

See all PubMed Citations (7)

Details of each submission

From Molecular Genetics Laboratory, Institute for Ophthalmic Research, SCV000700223.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966883.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

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.

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

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV004100328.1

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

#	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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