Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Molecular Genetics Laboratory, |
RCV000596662 | SCV000700223 | pathogenic | Achromatopsia | 2018-03-20 | criteria provided, single submitter | research | |
Eurofins Ntd Llc |
RCV000596729 | SCV000701669 | pathogenic | not provided | 2016-10-28 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular 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 | |
Ce |
RCV000596729 | SCV001249386 | pathogenic | not provided | 2018-11-01 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
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. |
Labcorp Genetics |
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 - |
RCV001814192 | SCV001755240 | pathogenic | Abnormality of the eye | 2021-07-10 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000596729 | SCV001802563 | pathogenic | not provided | 2024-01-19 | criteria provided, single submitter | clinical testing | Published functional studies suggest a damaging effect with impaired protein folding and trafficking (PMID: 18445228); 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: 3039450, 16961972, 19874885, 23972307, 17693388, 15712225, 11536077, 17652762, 24269407, 18445228, 24148654, 23362848, 28341476, 30682209, 28559085, 30653986, 30418171, 31290651, 31589614, 34426522, 35119454, 35052368, 34449556, 35456423) |
Revvity Omics, |
RCV001196267 | SCV002017391 | pathogenic | Achromatopsia 2 | 2020-07-17 | criteria provided, single submitter | clinical testing | |
Victorian Clinical Genetics Services, |
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, |
RCV000596662 | SCV004100328 | pathogenic | Achromatopsia | 2023-10-31 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV001075180 | SCV005071987 | pathogenic | Retinal dystrophy | 2018-01-01 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV001196267 | SCV005663334 | pathogenic | Achromatopsia 2 | 2024-03-18 | criteria provided, single submitter | clinical testing | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000678541 | SCV000804618 | uncertain significance | Macular dystrophy | 2016-09-01 | no assertion criteria provided | clinical testing |