ClinVar Miner

Submissions for variant NM_001386393.1(PANK2):c.887A>T (p.Lys296Ile)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV003388770 SCV004100561 uncertain significance Pigmentary pallidal degeneration criteria provided, single submitter clinical testing The missense variant p.K406I in PANK2 (NM_153638.3) has been previously reported in a patient of Indian origin with atypical patothenate kinase-associated neurodegeneration (Israni A et al,2017). The p.K406I variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between lysine and isoleucine. The p.K406I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The lysine residue at codon 406 of PANK2 is conserved in all mammalian species. The nucleotide c.1217 in PANK2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003388770 SCV004298019 likely pathogenic Pigmentary pallidal degeneration 2023-08-31 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PANK2 protein function. This missense change has been observed in individual(s) with autosomal recessive neurodegeneration with brain iron accumulation (PMID: 28681788, 34272103). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 406 of the PANK2 protein (p.Lys406Ile).

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