Submissions for variant NM_003560.4(PLA2G6):c.1743-2A>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226742	SCV003922903	likely pathogenic	Neurodegeneration with brain iron accumulation	2023-03-29	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.1743-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. One in silico prediction tool scores the variant as possibly damaging. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251116 control chromosomes. To our knowledge, no occurrence of c.1743-2A>G in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. Although a variant disrupting the same splice site, c.1743-1G>T, has been classified as pathogenic in ClinVar and reported in the literature in two compound heterozygous children with infantile neuroaxonal dystrophy (PMID: 31506141 and HGMD database). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003507490	SCV004269569	likely pathogenic	Infantile neuroaxonal dystrophy	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the PLA2G6 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 PLA2G6 are known to be pathogenic (PMID: 16783378, 18570303, 18799783, 22213678). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLA2G6-related conditions. ClinVar contains an entry for this variant (Variation ID: 2501145). 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.