rs104893615
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_001298.3(CNGA3):c.1669G>A(p.Gly557Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001298.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA3 | NM_001298.3 | c.1669G>A | p.Gly557Arg | missense_variant | 8/8 | ENST00000272602.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGA3 | ENST00000272602.7 | c.1669G>A | p.Gly557Arg | missense_variant | 8/8 | 1 | NM_001298.3 | A1 | |
CNGA3 | ENST00000436404.6 | c.1615G>A | p.Gly539Arg | missense_variant | 7/7 | 1 | P4 | ||
CNGA3 | ENST00000409937.1 | n.1822G>A | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251330Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135840
GnomAD4 exome AF: 0.0000752 AC: 110AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000701 AC XY: 51AN XY: 727238
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2023 | Published functional studies demonstrate a damaging effect with alteration of cGMP sensitivity, reduced calcium influx, and decreased cell surface expression compared to wild type (Reuter et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11536077, 32531858, 9662398, 25616768, 17693388, 18521937, 31456290, 31980526) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 557 of the CNGA3 protein (p.Gly557Arg). This variant is present in population databases (rs104893615, gnomAD 0.3%). This missense change has been observed in individual(s) with achromatopsia (PMID: 17265047, 18521937, 25616768; Invitae). 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: 9476). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CNGA3 function (PMID: 17693388, 18521937). For these reasons, this variant has been classified as Pathogenic. - |
Achromatopsia 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1998 | - - |
Achromatopsia Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 28, 2021 | The c.1669G>A (p.G557R) alteration is located in exon 8 (coding exon 7) of the CNGA3 gene. This alteration results from a G to A substitution at nucleotide position 1669, causing the glycine (G) at amino acid position 557 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (40/282722) total alleles studied. The highest observed frequency was 0.27% (28/10360) of Ashkenazi Jewish alleles. This alteration is one of the most common founder mutations in the Israeli population (Sharon, 2020). It has been reported in association with achromatopsia and other cone photoreceptor disorders in homozygotes and in heterozygotes with an additional CNGA3 alteration (Kohl, 1998; Wissinger, 2001; Wiszniewski, 2007; Reuter, 2008; Zelinger 2015; Matet, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 16, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 30, 2013 | The Gly557Arg variant in CNGA3 has been identified in 1 compound heterozygous individual with achromatopsia (Kohl 1998). Functional studies indicate this variant may alter protein function (Reuter 2008), though the assay is not clinically validated. In summary, although these data favor pathogenicity of the Gly557Arg variant, additional studies are needed to fully assess its clinical significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at