chr4-47937535-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_001379270.1(CNGA1):c.947C>T(p.Ser316Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. S316C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001379270.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA1 | NM_001379270.1 | c.947C>T | p.Ser316Phe | missense_variant | 11/11 | ENST00000514170.7 | |
LOC101927157 | NR_125879.1 | n.479-21489G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CNGA1 | ENST00000514170.7 | c.947C>T | p.Ser316Phe | missense_variant | 11/11 | 5 | NM_001379270.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00112 AC: 171AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00110 AC: 274AN: 249220Hom.: 0 AF XY: 0.00115 AC XY: 155AN XY: 135210
GnomAD4 exome AF: 0.00173 AC: 2528AN: 1461838Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 1232AN XY: 727216
GnomAD4 genome AF: 0.00112 AC: 171AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75AN XY: 74498
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2022 | 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: 22995991, 24265693, 25326637, 7479749, 31054281, 28981474, 31456290, 34426522, 31429209, 32531858, 35456422) - |
Likely 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 | Invitae | Jan 22, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the CNGA1 protein (p.Ser320Phe). This variant is present in population databases (rs62625014, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 7479749, 24265693, 25326637, 28981474; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Ser316Phe and p.Ser389Phe. ClinVar contains an entry for this variant (Variation ID: 16932). 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 not expected to disrupt CNGA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CNGA1 function (PMID: 7479749). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CNGA1: PM3:Very Strong, PP1:Strong, PM2:Supporting - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Retinitis pigmentosa Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 29, 2018 | The CNGA1 c.959C>T (p.Ser320Phe) missense variant, also referred to as c.1166C>T (p.Ser389Phe) and p.Ser316Phe, was found in a compound heterozygous state in six probands, including two sibling pairs, with autosomal recessive retinintis pigmentosa (Dryja et al. 1995; Eisenberger et al. 2013; Comander et al. 2017). Control data is unavailable for this variant, which is reported at a frequency of 0.001914 in the European (non-Finnish) population of the Genome Aggregation Database. Dryja et al. (1995) investigated channel function and found the p.Ser389Phe variant was similar to wild type for channel current and open times of the channel, however, the location was found to be intracellular, whereas wild type CNGA1 protein was located at the cell membrane. Based on the evidence, this variant is classified as likely pathogenic for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2023 | Variant summary: CNGA1 c.947C>T (p.Ser316Phe) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 249220 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGA1 causing Retinitis Pigmentosa phenotype (0.00088), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.947C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa, either at a compound heterozygous with second pathogenic variants or at a homozygous state (examples, Dryja_1995, Lee_CNGA1_2014, Weisschuh_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of frequencies of detecting functional cGMP-activated channel in HEK293 cells and the variant CNGA1 was predominantly retained inside the cell instead of being targeted to the plasma membrane (Dryja_1995). The following publications have been ascertained in the context of this evaluation (PMID: 7479749, 25326637, 32531858). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 11, 2018 | The p.Ser320Phe variant in CNGA1 (also described as p.Ser316Phe and p.Ser389Phe in the literature) has been reported in compound heterozygous state in 4 individ uals with autosomal recessive retinitis pigmentosa (RP), and segregated with dis ease in 2 affected relatives from 2 families (Dryja 1995, Eisenberger 2013, Coma nder 2017). In vitro functional studies provide some evidence that the p.Ser320P he variant may impact protein function (Dryja 1995). This variant has been repor ted in ClinVar (Variation ID: 424770) and has been identified in 0.19% (242/1264 08) Of European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs62625014). Please note that this frequency is low enough to be consistent with the frequency of RP in the general population. In summary, although additional studies are required to fully establish its clin ical significance, the p.Ser320Phe variant is likely pathogenic for RP in an aut osomal recessive manner. ACMG/AMP Criteria applied: PM3_Strong; PP1; PS3_Support ing. - |
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Retinitis pigmentosa 49 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 29, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 24, 1995 | - - |
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CNGA1 c.1166C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP1, PS3, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 12, 2022 | - - |
Macular dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP5. - |
Cone-rod dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Retinitis pigmentosa;C3151059:Retinitis pigmentosa 49 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 04, 2022 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 16, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at