Submissions for variant NM_001386393.1(PANK2):c.1112G>A (p.Arg371Gln)

dbSNP: rs1241995212

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	RCV002240129	SCV002511978	uncertain significance	not specified	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: PANK2 c.1442G>A (p.Arg481Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1442G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Neurodegeneration with brain iron accumulation (NBIA) (example, Hartig_2006, Chang_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV003388625	SCV004100411	uncertain significance	Pigmentary pallidal degeneration		criteria provided, single submitter	clinical testing	The missense variant p.R481Q in PANK2 (NM_153638.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.R481Q variant is observed in 1/30,616 (0.0033%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.R481Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamine residue at codon 481 of PANK2 is only present in a single other mammalian species: Armadillo. The nucleotide c.1442 in PANK2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.