ClinVar Miner

Submissions for variant NM_001079878.2(CNGA3):c.101+1G>A (rs147118493)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2016-03-15 criteria provided, single submitter clinical testing The c.101+1G>A pathogenic variant in the CNGA3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.101+1G>A variant was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.101+1G>A as a pathogenic variant.
Illumina Clinical Services Laboratory,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.
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 RCV001002958 SCV001161001 pathogenic Cone-rod degeneration 2019-06-23 no assertion criteria provided research

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