Submissions for variant NM_018238.4(AGK):c.1047-2A>T

dbSNP: rs886041491

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000279504	SCV000330156	pathogenic	not provided	2018-10-11	criteria provided, single submitter	clinical testing	The c.1047-2A>T variant in the AGK 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 acceptor site in intron 14. 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.1047-2A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1047-2A>T as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765578	SCV004576187	likely pathogenic	Sengers syndrome; Cataract 38	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 of the AGK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGK are known to be pathogenic (PMID: 22284826). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AGK-related conditions. ClinVar contains an entry for this variant (Variation ID: 280255). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.