Submissions for variant NM_001386393.1(PANK2):c.-21G>T

dbSNP: rs780551883

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000357905	SCV000337378	pathogenic	not provided	2015-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469097	SCV002766544	likely pathogenic	Pigmentary pallidal degeneration	2022-11-29	criteria provided, single submitter	clinical testing	Variant summary: PANK2 c.310G>T (p.Glu104X; NM_153638.3) results in a premature termination codon within exon 1, 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. This variant is located in the 5-prime untranslated region of other PANK2 transcripts. The PANK2 protein translated from the most 5-prime start encodes a precursor protein consisting of 570 residues, which is sequentially cleaved by peptidase(s) to initially yield a transient intermediate protein (cleavage between residues 31 and 32), and finally a 48-kDa mature protein (cleavage between residues 140 and 141) (PMIDs: 15659606, 16272150). To our knowledge, truncation variants upstream or in close proximity to p.Glu104X have not been reported in patients in the literature, while missense variants within this region are cited in online databases as VUS or likely benign/benign. While the variant is not located within the region of the mature PANK2 protein, it is nevertheless located in the region translating to the precursor protein, and it would still be expected to result in truncation of the encoded protein or absence of the protein due to nonsense mediated decay, as pertaining to the NM_153638.3 transcript. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 178494 control chromosomes (gnomAD). To our knowledge, no occurrence of c.310G>T in individuals affected with Pantothenate Kinase-Associated Neurodegeneration and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.