Submissions for variant NM_001298.3(CNGA3):c.101+1G>A

gnomAD frequency: 0.00014  dbSNP: rs147118493

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190571	SCV000245590	likely pathogenic	Achromatopsia 2	2014-10-20	criteria provided, single submitter	clinical testing	The c.101+1G>A variant in CNGA3 has not been previously reported in individuals with achromatopsia, but has been identified in 0.08% (7/8600) of European American chromosomes and 0.02% (1/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs147118493). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Complete loss of CNGA3 function is an established disease mechanism in individuals with achromatopsia (Wissinger 2001). In summary, although additional studies are required to fully establish its clinical significance, the c.101+1G>A variant is likely pathogenic.
GeneDx	RCV000323992	SCV000330354	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11536077, 30289319, 31456290, 31980526, 35332618)
Illumina Laboratory Services, Illumina	RCV000190571	SCV000914946	uncertain significance	Achromatopsia 2	2018-11-15	criteria provided, single submitter	clinical testing	The CNGA3 c.101+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.101+1G>A variant has been reported in one study and found in three unrelated individuals from consanguineous families affected with achromatopsia in a homozygous state (Abdelkader et al. 2018). Two of these individuals were also homozygous for a stop-gained variant, p.Arg221Ter. Control data are unavailable for this variant, which is reported at a frequency of 0.005956 in the Ashkenazi Jewish population of the Genome Aggregation Database. Due to the potential impact of splice donor variants and the limited evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000190571	SCV001524041	uncertain significance	Achromatopsia 2	2020-07-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000323992	SCV001687892	likely benign	not provided	2023-12-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000190571	SCV003826890	likely pathogenic	Achromatopsia 2	2022-09-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000190571	SCV004810153	uncertain significance	Achromatopsia 2	2024-04-04	criteria provided, single submitter	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000190571	SCV001142320	pathogenic	Achromatopsia 2	2020-01-06	no assertion criteria provided	curation	NG_009097.1(NM_001298.2):c.101+1G>A in the CNGA3 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The CNGA3 c.101+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in one study and found in three unrelated individuals from consanguineous families affected with achromatopsia in a homozygous state (PMID: 30289319). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP4.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV002267730	SCV001161001	pathogenic	Cone-rod dystrophy	2019-06-23	no assertion criteria provided	research