Submissions for variant NM_001386393.1(PANK2):c.740G>C (p.Arg247Pro)

dbSNP: rs754521581

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000990272	SCV001141200	likely pathogenic	Pigmentary pallidal degeneration	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000990272	SCV001391682	pathogenic	Pigmentary pallidal degeneration	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 357 of the PANK2 protein (p.Arg357Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of neurodegeneration with brain iron accumulation (PMID: 15911822; Invitae). This variant is also known as c.G740C, p.R247P. ClinVar contains an entry for this variant (Variation ID: 803594). 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. 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: 16437574, 22221393, 28680084). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000990272	SCV002599022	likely pathogenic	Pigmentary pallidal degeneration	2022-09-22	criteria provided, single submitter	clinical testing	Variant summary: PANK2 c.1070G>C (p.Arg357Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251366 control chromosomes. c.1070G>C has been reported in the literature in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (Pelleccia_2005). These data indicate that the variant is likely to be associated with disease. Additionally, two other variants at the same codon have been reported in association with Pantothenate kinase-associated neurodegeneration in HGMD (R357Q, R357W), supporting pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV003151260	SCV003839807	likely pathogenic	not provided	2022-04-01	no assertion criteria provided	clinical testing	DNA sequence analysis of the PANK2 gene demonstrated a sequence change, c.1070G>C, in exon 3 that results in an amino acid change, p.Arg357Pro. The p.Arg357Pro change affects a poorly conserved amino acid residue located in a domain of the PANK2 protein that is known to be functional. The p.Arg357Pro substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has previously been described in the literature in the compound heterozygous and homozygous states in individuals with classic PKAN phenotype including the eye of the tiger sign (PMID: 15911822). Additionally, different sequence changes affecting the same amino acid residue (p.Arg357Gln, p.Arg357Trp) have been described in individuals with CEP290-related disorders (PMID: 16437574, 22221393, 28680084). This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.0008% (dbSNP rs754521581). Based on these evidences, this sequence change is classified as likely pathogenic, however functional studies have not been performed to prove this conclusively.