Submissions for variant NM_003560.4(PLA2G6):c.2287C>T (p.Gln763Ter)

gnomAD frequency: 0.00003  dbSNP: rs373493102

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	RCV001532992	SCV001748827	likely pathogenic	Neurodegeneration with brain iron accumulation	2021-06-23	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.2287C>T (p.Gln763X) 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 cited in ClinVar as pathogenic by multiple submitters (e.g. c.2370T>G, p.Tyr790X; c.2370_2371delTG, p.Tyr790X) and are reported as disease causing mutations in HGMD (e.g. c.2389C>T, p.Q797X). The variant allele was found at a frequency of 8e-06 in 249528 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2287C>T 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002568913	SCV003761461	likely pathogenic	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Gln763Ter variant in PLA2G6 has not been previously reported in the literature in individuals with PLA2G6-associated neurodegeneration but has been identified in 0.008% (2/24686) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs373493102). 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#: 1177288) and has been interpreted as likely pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp). This nonsense variant leads to a premature termination codon at position 763. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Truncating variants downstream of this variant (c.2370T>G and c.2370_2371delTG) are pathogenic/likely pathogenic, which implies this region is critical to protein function. Loss of function of the PLA2G6 gene is an established disease mechanism in PLA2G6-associated neurodegeneration. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1_strong, PM2 (Richards 2015).