rs104893620
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001298.3(CNGA3):c.829C>T(p.Arg277Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277H) has been classified as Pathogenic.
Frequency
Consequence
NM_001298.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA3 | NM_001298.3 | c.829C>T | p.Arg277Cys | missense_variant | 8/8 | ENST00000272602.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGA3 | ENST00000272602.7 | c.829C>T | p.Arg277Cys | missense_variant | 8/8 | 1 | NM_001298.3 | A1 | |
CNGA3 | ENST00000436404.6 | c.775C>T | p.Arg259Cys | missense_variant | 7/7 | 1 | P4 | ||
CNGA3 | ENST00000409937.1 | n.982C>T | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251350Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135862
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47AN XY: 727240
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2022 | Published functional studies demonstrate a damaging effect as R277C impaired channel activity compared to wild type CNGA3 (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: 20238023, 21912902, 14736794, 14757870, 15712225, 16961972, 18521937, 15743887, 21911670, 26992781, 19592100, 24049715, 18445228, 23082193, 30682209, 30653986, 30418171, 31456290, 17693388, 11536077) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 277 of the CNGA3 protein (p.Arg277Cys). This variant is present in population databases (rs104893620, gnomAD 0.02%). This missense change has been observed in individuals with achromatopsia and cone dystrophy (PMID: 11536077). ClinVar contains an entry for this variant (Variation ID: 9481). 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: 20238023). This variant disrupts the p.Arg277 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11536077, 17693388, 26992781). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2018 | - - |
Achromatopsia 2 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 09, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Achromatopsia Pathogenic:2
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Mar 20, 2018 | - - |
Macular degeneration;C0085636:Photophobia;C0234629:Color vision defect Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at