Submissions for variant NM_001386393.1(PANK2):c.739C>T (p.Arg247Trp)

gnomAD frequency: 0.00002  dbSNP: rs753376100

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414787	SCV000492904	pathogenic	Neurodegeneration	2015-04-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196627	SCV001367239	pathogenic	Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401407	SCV004122519	pathogenic	Pigmentary pallidal degeneration	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: PANK2 c.1069C>T (p.Arg357Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251370 control chromosomes. c.1069C>T has been reported, at a homozygous state, in the literature in multiple individuals affected with Pantothenate Kinase-Associated Neurodegeneration (examples, Valentino_2006, Hartig_2006, Dezfouli_2012, Angural_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28680084, 24250886, 16437574, 16149094). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003401407	SCV004298018	pathogenic	Pigmentary pallidal degeneration	2023-05-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg357 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15911822; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PANK2 protein function. ClinVar contains an entry for this variant (Variation ID: 374127). This missense change has been observed in individual(s) with clinical features of pantothenate kinase-associated neurodegeneration (PMID: 16437574, 23166001, 28680084, 29801903). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs753376100, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 357 of the PANK2 protein (p.Arg357Trp).