Submissions for variant NM_001298.3(CNGA3):c.682G>A (p.Glu228Lys)

gnomAD frequency: 0.00049  dbSNP: rs147415641

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778101	SCV000432718	uncertain significance	Achromatopsia 2	2017-04-27	criteria provided, single submitter	clinical testing	The CNGA3 c.682G>A (p.Glu228Lys) variant was identified in a homozygous state in two siblings with achromatopsia (Reuter et al. 2008). A third individual was found to carry the p.Glu228Lys variant in a compound heterozygous state with a second missense variant along with a homozygous missense variant in the CNGB3 gene (Thiadens et al. 2010). The p.Glu228Lys variant was absent from 100 controls and is reported at a frequency of 0.01005 in the South Asian population of the Exome Aggregation Consortium. Expression of wild type and p.Glu228Lys forms of the A3 channel in HEK293 cells revealed that p.Glu228Lys channels were localized intracellularly instead of at the cell membrane and showed decreased channel density compared to wild type. Based on the evidence, the p.Glu228Lys 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.
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000273159	SCV000700218	pathogenic	Achromatopsia	2018-03-20	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000733679	SCV000861772	likely benign	not specified	2018-06-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000778101	SCV001435234	uncertain significance	Achromatopsia 2		criteria provided, single submitter	research	The homozygous p.Glu228Lys variant in CNGA3 has been identified in 2 siblings from 1 family with incomplete achromatopsia and in the heterozygous state in an individual with a different eye phenotype and other missense variants (PMID: 18521937, 20079539), and has been identified in >1% of South Asian chromosomes and a homozygote by ExAC (http://gnomad.broadinstitute.org/). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Glu228Lys variant may slightly impact protein function (PMID: 18521937). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain.
Invitae	RCV001512908	SCV001720408	benign	not provided	2023-12-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000733679	SCV004020821	uncertain significance	not specified	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: CNGA3 c.682G>A (p.Glu228Lys) results in a 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 0.0014 in 251304 control chromosomes in the gnomAD database, including 2 homozygotes. c.682G>A was found in homozygous state in two siblings with incomplete Achromatopsia (Reuter_ 2008), and in individuals affected with cone dystrophy (Thiadens _2010 and Hitti-malin_CNGA3_HM_2022). In at-least, one of these individuals affected with cone dystrophy authors reported a homozygous variant in CNGB3 (Thiadens _2010). These report(s) do not provide unequivocal conclusions about association of the variant with Achromatopsia 2. At least one publication reports experimental evidence evaluating an impact on protein function. However, it does not provide strong conclusions about the variant association with the disease (Reuter_ 2008). The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 30418171, 36259723, 27535533, 18521937, 26036949, 31456290, 32913385, 20079539). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2), pathogenic/likely pathogenic (n=2) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000273159	SCV001161005	likely pathogenic	Achromatopsia	2019-06-23	no assertion criteria provided	research