Submissions for variant NM_003560.4(PLA2G6):c.1262del (p.Val421fs)

gnomAD frequency: 0.00002  dbSNP: rs1282370486

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808605	SCV000948719	pathogenic	Infantile neuroaxonal dystrophy	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val421Alafs*26) in the PLA2G6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLA2G6 are known to be pathogenic (PMID: 16783378, 18570303, 18799783, 22213678). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 652932). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768671	SCV005380950	pathogenic	Neurodegeneration with brain iron accumulation	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.1262delT (p.Val421AlafsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250816 control chromosomes. To our knowledge, no occurrence of c.1262delT in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 652932). Based on the evidence outlined above, the variant was classified as pathogenic.