Submissions for variant NM_001386393.1(PANK2):c.498_499del (p.Cys166fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV003338055	SCV004046936	likely pathogenic	Pigmentary pallidal degeneration		criteria provided, single submitter	clinical testing	The frameshift c.498_499del (p.Cys166TrpfsTer15) in the PANK2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Cysteine 166, changes this amino acid to Tryptophan residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Cys166TrpfsTer15. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic.
Invitae	RCV003338055	SCV004298014	pathogenic	Pigmentary pallidal degeneration	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys276Trpfs*15) in the PANK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PANK2 are known to be pathogenic (PMID: 11479594, 12510040). This variant is present in population databases (rs748911913, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 20925075, 28567303). This variant is also known as c.498_499delITG. 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.