Submissions for variant NM_153638.4(PANK2):c.42_67del (p.Ala15fs)

dbSNP: rs760822872

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479319	SCV000572005	likely pathogenic	not provided	2016-10-27	criteria provided, single submitter	clinical testing	The c.42_67del26 variant in the PANK2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.42_67del26 variant causes a frameshift starting with codon Alanine 15, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Ala15ThrfsX24. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.42_67del26 variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.42_67del26 as a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731712	SCV001983706	likely pathogenic	Pigmentary pallidal degeneration	2021-09-02	criteria provided, single submitter	clinical testing	Variant summary: PANK2 c.42_67del26 (p.Ala15ThrfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.3e-05 in 173688 control chromosomes (gnomAD). To our knowledge, no occurrence of c.42_67del26 in individuals affected with Pantothenate Kinase-Associated Neurodegeneration and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001731712	SCV002251598	uncertain significance	Pigmentary pallidal degeneration	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala15Thrfs*24) in the PANK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 556 amino acid(s) of the PANK2 protein. This variant is present in population databases (rs760822872, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422512). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.