ClinVar Miner

Submissions for variant NM_001386393.1(PANK2):c.350A>G (p.Tyr117Cys)

gnomAD frequency: 0.00001  dbSNP: rs1555787646
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544004 SCV000626804 pathogenic Pigmentary pallidal degeneration 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 227 of the PANK2 protein (p.Tyr227Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pantothenate kinase-associated neurodegeneration (PMID: 17903678, 22127788, 22682757, 25915509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 456525). 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 RCV000544004 SCV002547704 pathogenic Pigmentary pallidal degeneration 2022-05-19 criteria provided, single submitter clinical testing Variant summary: PANK2 c.680A>G (p.Tyr227Cys) 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 was absent in 251270 control chromosomes. c.680A>G has been reported in the literature in multiple individuals affected with Pantothenate Kinase-Associated Neurodegeneration (example, Saleheen_2007, Delgado_2012, Stoeler_2020). 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. One clinical diagnostic laboratory and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV002466529 SCV002762246 pathogenic not provided 2022-12-09 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22682757, 17903678, 31589614, 25915509)
GeneReviews RCV000544004 SCV002014768 not provided Pigmentary pallidal degeneration no assertion provided literature only
OMIM RCV000544004 SCV004801286 pathogenic Pigmentary pallidal degeneration 2024-03-13 no assertion criteria provided literature only

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