Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001851655 | SCV002162930 | likely pathogenic | Pigmentary pallidal degeneration | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the PANK2 protein (p.Thr234Ala). This variant is present in population databases (rs137852965, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16023068, 26547561). This variant is also known as c.400A>G (p.T124A) or c.370A>G. ClinVar contains an entry for this variant (Variation ID: 4554). 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. Experimental studies have shown that this missense change does not substantially affect PANK2 function (PMID: 15659606). This variant disrupts the p.Thr234 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 23166001), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003234892 | SCV003934223 | uncertain significance | not specified | 2023-05-09 | criteria provided, single submitter | clinical testing | Variant summary: PANK2 c.700A>G (p.Thr234Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 251292 control chromosomes. c.700A>G has been reported in the literature as a biallelic compound heterozygous genotyp in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (example, Zhou_2001, cited in Hayflick_2003 and Thomas_2004; Egan_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kotzbauer_2005). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 28113101, 16023068, 12510040, 15659606, 16450344, 27544236, 14743358, 26547561, 16272150, 11479594). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| OMIM | RCV001851655 | SCV000024990 | pathogenic | Pigmentary pallidal degeneration | 2001-08-01 | no assertion criteria provided | literature only |