Submissions for variant NM_001298.3(CNGA3):c.1557G>A (p.Met519Ile)

gnomAD frequency: 0.00004  dbSNP: rs199655686

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000322792	SCV000343337	uncertain significance	not provided	2016-07-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000322792	SCV002243415	pathogenic	not provided	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 519 of the CNGA3 protein (p.Met519Ile). This variant is present in population databases (rs199655686, gnomAD 0.01%). This missense change has been observed in individual(s) with achromatopsia and/or CNGA3-related conditions (PMID: 27208204, 30682209; internal data). 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: 236463). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CNGA3 protein function with a positive predictive value of 95%. This variant disrupts the p.Met519 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 26992781, 27208204, 30682209), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225371	SCV000282569	uncertain significance	Retinal dystrophy		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678543	SCV000804620	uncertain significance	Achromatopsia 2	2016-09-01	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000322792	SCV001923131	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000322792	SCV001966725	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000322792	SCV001979520	likely pathogenic	not provided		no assertion criteria provided	clinical testing