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

gnomAD frequency: 0.00036  dbSNP: rs141386891

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000596662	SCV000700223	pathogenic	Achromatopsia	2018-03-20	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000596729	SCV000701669	pathogenic	not provided	2016-10-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000596662	SCV000966883	pathogenic	Achromatopsia	2018-06-05	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV001075180	SCV001240792	pathogenic	Retinal dystrophy	2018-11-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000596729	SCV001249386	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196267	SCV001366833	pathogenic	Achromatopsia 2	2019-09-12	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
Invitae	RCV000596729	SCV001389552	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 427 of the CNGA3 protein (p.Arg427Cys). This variant is present in population databases (rs141386891, gnomAD 0.2%). This missense change has been observed in individual(s) with achromatopsia or cone dystrophy (PMID: 11536077, 18445228, 23972307, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 497256). 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: 18445228). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814192	SCV001755240	pathogenic	Abnormality of the eye	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000596729	SCV001802563	pathogenic	not provided	2021-05-24	criteria provided, single submitter	clinical testing	Published functional studies of this variant demonstrates that cGMP maximum currents of mutant channels were reduced, and the chemical chaperone glycerol significantly enhanced surface expression of mutant channels and macroscopic currents, which may indicate impaired folding and trafficking of the mutant channel protein (Koeppen et al., 2008); 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: 31290651, 30418171, 30653986, 28559085, 30682209, 28341476, 23362848, 24148654, 18445228, 23972307, 24269407, 17652762, 11536077, 15712225, 17693388, 16961972, 19874885, 3039450)
Revvity Omics, Revvity	RCV001196267	SCV002017391	pathogenic	Achromatopsia 2	2020-07-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001196267	SCV002766657	pathogenic	Achromatopsia 2	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with achromatopsia 2 (MIM#216900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been described within sibling pairs (PMID: 30682209). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (108 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg427Leu)) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and observed in compound heterozygous individuals with achromatopsia and retinal dystrophy (ClinVar, LOVD, PMID: 30653986). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000596662	SCV004100328	pathogenic	Achromatopsia	2023-10-31	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678541	SCV000804618	uncertain significance	Macular dystrophy	2016-09-01	no assertion criteria provided	clinical testing