Submissions for variant NM_003560.4(PLA2G6):c.2277-2A>C

dbSNP: rs552606315

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599329	SCV000710684	likely pathogenic	not provided	2018-11-02	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the PLA2G6 gene. The c.2277-2A>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 16. 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. Furthermore, the c.2277-2A>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000815114	SCV000955558	uncertain significance	Infantile neuroaxonal dystrophy	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 16 of the PLA2G6 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs552606315, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 25348461; Invitae). ClinVar contains an entry for this variant (Variation ID: 504363). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002532704	SCV003761462	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The c.2277-2A>C variant in PLA2G6 has not been previously reported in the literature in individuals with PLA2G6-associated neurodegeneration but has been identified in 0.003% (1/34446) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs552606315). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 504363) and has been interpreted as likely pathogenic by GeneDx and as a variant of uncertain significance by Invitae. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the PLA2G6 gene is an established disease mechanism in PLA2G6-associated neurodegeneration. In summary, the clinical significance of the c.2277-2A>C variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PM2_supporting (Richards 2015).