Submissions for variant NM_003560.4(PLA2G6):c.1294del (p.His432fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002283379	SCV002571869	likely pathogenic	Neurodegeneration with brain iron accumulation	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.1294delC (p.His432IlefsX15) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250880 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1294delC in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. 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	RCV003507404	SCV004305130	pathogenic	Infantile neuroaxonal dystrophy	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His432Ilefs*15) 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 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: 1705054). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004047570	SCV005005448	uncertain significance	Inborn genetic diseases	2023-11-07	criteria provided, single submitter	clinical testing	The c.1294delC (p.H432Ifs*15) alteration, located in exon 9 (coding exon 8) of the PLA2G6 gene, consists of a deletion of one nucleotide at position 1294, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This region of the PLA2G6 gene is excluded from biologically relevant transcript isoforms. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/250880) total alleles studied. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.