rs146195955
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_001298.3(CNGA3):c.967G>C(p.Ala323Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A323D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001298.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA3 | NM_001298.3 | c.967G>C | p.Ala323Pro | missense_variant | 8/8 | ENST00000272602.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGA3 | ENST00000272602.7 | c.967G>C | p.Ala323Pro | missense_variant | 8/8 | 1 | NM_001298.3 | A1 | |
CNGA3 | ENST00000436404.6 | c.913G>C | p.Ala305Pro | missense_variant | 7/7 | 1 | P4 | ||
CNGA3 | ENST00000409937.1 | n.1120G>C | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000302 AC: 46AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251488Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135920
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727246
GnomAD4 genome ? AF: 0.000302 AC: 46AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74430
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2023 | 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: 31725702, 30289319, 32581362, 32783370, 28041643) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 323 of the CNGA3 protein (p.Ala323Pro). This variant is present in population databases (rs146195955, gnomAD 0.09%). This missense change has been observed in individual(s) with cone rod dystrophy and achromatopsia (PMID: 28041643, 30289319; 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: 284032). 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%. This variant disrupts the p.Ala323 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 26493561), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 12, 2018 | - - |
Achromatopsia 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2023 | Variant summary: CNGA3 c.967G>C (p.Ala323Pro) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251488 control chromosomes. c.967G>C has been reported in the literature in multiple individuals affected with Achromatopsia and other CNGA3-related diseases including rod monochromacy and macular degenerations, either being seen with second pathogenic variants or being homozygous (example: Hitti-malin_2022, Mejecase_2020, Sun_2020, Solaki_2022). These data indicate that the variant is very likely to be associated with Achromatopsia 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36259723, 32783370, 32913385, 35332618). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=4; Likely pathogenic, n=1; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 31, 2019 | - - |
Cone dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at