Submissions for variant NM_001298.3(CNGA3):c.1228C>T (p.Arg410Trp)

gnomAD frequency: 0.00004  dbSNP: rs137852608

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000010087	SCV000914948	pathogenic	Achromatopsia 2	2018-04-25	criteria provided, single submitter	clinical testing	The CNGA3 c.1228C>T (p.Arg410Trp) variant was reported in six individuals with achromatopsia, including one individual who carries the variant in a homozygous state and five individuals, including a sibling pair, who carry the variant in a compound heterozygous state (Kohl et al. 1998; Wissinger et al. 2001; Nishiguchi et al. 2005; Genead et al. 2011; Liang et al. 2015). The variant was also identified in a homozygous state in an individual with cone dystrophy (Dockery et al. 2017). The p.Arg410Trp variant was absent from 190 control individuals (Kohl et al. 1998; Nishiguchi et al. 2005) and is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. When transfected in HEK-293 cells, the p.Arg410Trp variant showed no cGMP channel activity, in contrast to the wild type protein, which showed maximum activity at the same vector concentration, and preliminary studies suggested that the channel function was not rescued when the p.Arg410Trp variant was co-expressed with wild type (Muraki-Oda et al. 2007). Tanaka et al. (2015) demonstrated that the canine orthologous variant, p.Arg424Trp, results in complete loss of channel activity and cone function in vivo, and structural modeling and molecular dynamics simulations suggested the variant disrupted a salt bridge formation. Based on the collective evidence, the p.Arg410Trp variant is classified as pathogenic for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001052998	SCV001217239	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the CNGA3 protein (p.Arg410Trp). This variant is present in population databases (rs137852608, gnomAD 0.009%). This missense change has been observed in individuals with achromatopsia or cone dystrophy (PMID: 9662398, 11536077, 25637600, 29099798, 30337596). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg411Trp. ClinVar contains an entry for this variant (Variation ID: 9479). 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.
Blueprint Genetics	RCV001075289	SCV001240905	pathogenic	Retinal dystrophy	2017-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001052998	SCV001872648	pathogenic	not provided	2021-08-10	criteria provided, single submitter	clinical testing	Published functional studies showed no cGMP-activated current by patch-clamp recording technique, suggesting R410W may cause a loss of function of CNG channels (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: 9662398, 17693388, 30682209, 30337596, 31589614, 29099798, 25637600, 21778272, 26407004, 15712225, 11536077, 12187427, 12876837, 27040408)
OMIM	RCV000010087	SCV000030308	pathogenic	Achromatopsia 2	1998-07-01	no assertion criteria provided	literature only