Submissions for variant NM_001386393.1(PANK2):c.803A>G (p.Asp268Gly)

gnomAD frequency: 0.00005  dbSNP: rs562740927

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490498	SCV000267434	uncertain significance	Pigmentary pallidal degeneration	2016-03-18	criteria provided, single submitter	reference population
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490498	SCV001677398	pathogenic	Pigmentary pallidal degeneration	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 378 of the PANK2 protein (p.Asp378Gly). This variant is present in population databases (rs562740927, gnomAD 0.3%). This missense change has been observed in individual(s) with pantothenate kinase-associated neurodegeneration (PMID: 15747360, 20193558, 26828213). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Asp268Gly. ClinVar contains an entry for this variant (Variation ID: 225428). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229192	SCV002511977	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: PANK2 c.1133A>G (p.Asp378Gly) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251536 control chromosomes, predominantly at a frequency of 0.0031 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PANK2 causing Pantothenate Kinase-Associated Neurodegeneration phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1133A>G has been reported in combination with another pathogenic variant in the literature in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (Zhang_2005, Wu_2009, Mak_2011, Lim_2011, Kim_2012, Pan_2020, Yang_2022) and this variant is commonly affected alleles in Chinese origin (Zhang_2005, Wu_2009, Ma_2014, Ma_208, Pan_2020). These data indicate that the variant may 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: 35246191, 22547525, 24868354, 22103354, 24689511, 29801903, 21198414, 32310012, 20076801, 19224615, 15747360, 30681573). ClinVar contains an entry for this variant (Variation ID: 225428). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.