Submissions for variant NM_001298.3(CNGA3):c.1641C>A (p.Phe547Leu)

dbSNP: rs104893617

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415000	SCV000492976	likely pathogenic	Monochromacy	2014-07-21	criteria provided, single submitter	clinical testing
Invitae	RCV001055558	SCV001219956	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 547 of the CNGA3 protein (p.Phe547Leu). This variant is present in population databases (rs104893617, gnomAD 0.07%). This missense change has been observed in individual(s) with achromatopsia (PMID: 9662398, 11536077, 14757870, 23972307, 30682209). 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: 9478). 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	RCV001074686	SCV001240279	pathogenic	Retinal dystrophy	2019-03-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001055558	SCV001249389	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	CNGA3: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000010086	SCV001369955	pathogenic	Achromatopsia 2	2018-11-12	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PP3,PP4. This variant was detected in homozygous state.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001055558	SCV001762265	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001055558	SCV001768121	pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate loss of electrophysiological activity in the mutant channel compared to wild type (Matveev et al., 2010; 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: 16961972, 31429209, 32531858, 23972307, 20088482, 9662398, 17693388, 18521937, 25168900, 27040408, 19592100, 11536077, 14757870, 24148654, 16319819, 30682209, 30653986, 31456290, 33562422, 31589614, 34426522, 34449556)
Neuberg Centre For Genomic Medicine, NCGM	RCV000010086	SCV002073303	pathogenic	Achromatopsia 2		criteria provided, single submitter	clinical testing	The missense variant p.F547L in CNGA3 (NM_001298.3) has been reported previously in homozygous as well as compound heterozygous state in affected indviduals (Fahim AT et al; Georgiou M et al).It is known to affect protein function (Muraki-Oda S et al). It has been submitted to ClinVar as Pathogenic/Likely Pathogenic. It is present in 45 alleles in heterozygous state in the gnomad database (0.1%) as well as it has been observed in homozygous state in one individual. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010086	SCV004099714	pathogenic	Achromatopsia 2	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: CNGA3 c.1641C>A (p.Phe547Leu) results in a non-conservative amino acid change located in the cyclic nucleotide-binding domain (IPR000595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251308 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1641C>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Achromatopsia 2 (e.g., Sun_2020). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 32913385). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000010086	SCV000030307	pathogenic	Achromatopsia 2	2001-10-01	no assertion criteria provided	literature only
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002970	SCV001161018	pathogenic	Achromatopsia	2019-06-23	no assertion criteria provided	research