Submissions for variant NM_001298.3(CNGA3):c.811C>G (p.Pro271Ala)

gnomAD frequency: 0.00022  dbSNP: rs149802213

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000734467	SCV000862612	uncertain significance	not provided	2018-08-09	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074985	SCV001240594	pathogenic	Retinal dystrophy	2017-11-12	criteria provided, single submitter	clinical testing
Invitae	RCV000734467	SCV001381015	pathogenic	not provided	2023-07-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro271 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 30682209), which suggests that this may be a clinically significant amino acid residue. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CNGA3 protein function. ClinVar contains an entry for this variant (Variation ID: 598143). This missense change has been observed in individual(s) with retinal disease (PMID: 25616768; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs149802213, gnomAD 0.03%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 271 of the CNGA3 protein (p.Pro271Ala).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001261952	SCV001439303	pathogenic	Achromatopsia 2	2020-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000734467	SCV001987778	uncertain significance	not provided	2019-10-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in five members of one family with achromatopsia who also harbored a second variant in the CNGA3 gene (Zelinger et al., 2015); This variant is associated with the following publications: (PMID: 25616768, 31456290)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001261952	SCV003934771	likely pathogenic	Achromatopsia 2	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: CNGA3 c.811C>G (p.Pro271Ala) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence, altering a highly conserved residue (HGMD) in which another missense variant is classified as likely pathogenic in ClinVar (p.Pro271Thr). 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 0.00012 in 251424 control chromosomes. c.811C>G has been reported in the literature in individuals affected with Achromatopsia and cone-rod dystrophy who were reported as compound heterozygous with other (likely) pathogenic variants (Zellinger_2015, Sharon_2020, Del Pozo-Valero_2022, Sun_2020). These data indicate that the variant is likely associated with disease. 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: 25616768, 31456290, 35119454, 32913385). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2), likely pathogenic (n=1), or pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002962	SCV001161006	likely pathogenic	Achromatopsia	2019-06-23	no assertion criteria provided	research