ClinVar Miner

Submissions for variant NM_001386393.1(PANK2):c.526C>T (p.Arg176Cys)

gnomAD frequency: 0.00001  dbSNP: rs137852962
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000004811 SCV003443940 pathogenic Pigmentary pallidal degeneration 2023-08-30 criteria provided, single submitter clinical testing Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PANK2 function (PMID: 16272150). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 286 of the PANK2 protein (p.Arg286Cys). This variant is present in population databases (rs137852962, gnomAD 0.006%). This missense change has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 11479594, 16437574, 22221393). This variant is also known as R176C. ClinVar contains an entry for this variant (Variation ID: 4551). 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. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV000004811 SCV005438809 likely pathogenic Pigmentary pallidal degeneration 2023-07-22 criteria provided, single submitter clinical testing The observed missense c.526C>Tp.Arg176Cys variant in PANK2 gene has been previously observed in homozygous/compound heterozygous states in multiple individuals affected with neurodegenrative disorders associated with iron accumulation. Experimental studies on this variant in PANK2 gene provides insufficient evidence. This variant is present with allele frequency 0.0008% in the gnomAD Exomes. It has been submitted to ClinVar as Pathogenic variant. Multiple lines of computational evidences Polyphen - Probably damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg176Cys in PANK2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 176 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.
OMIM RCV000004811 SCV000024987 pathogenic Pigmentary pallidal degeneration 2001-08-01 no assertion criteria provided literature only

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