Submissions for variant NM_001386393.1(PANK2):c.651+3A>G

dbSNP: rs1131691472

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494403	SCV000582190	likely pathogenic	not provided	2015-10-15	criteria provided, single submitter	clinical testing	The c.981+3A>G variant in the PANK2 gene has been reported previously in two individuals with early-onset, rapidly progressive (classic) pantothenate kinase–associated neurodegeneration (Hayflick et al., 2003). Splice predictor models are inconsistent in their predictions as to how c.981+3A>G impacts splicing. Xiong et al (2014) reported c.981+3A>G is predicted to induce a splicing change. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.981+3A>G 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. Given the available evidence, the c.981+3A>G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851354	SCV002198883	uncertain significance	Pigmentary pallidal degeneration	2023-08-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the PANK2 gene. It does not directly change the encoded amino acid sequence of the PANK2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of neurodegeneration with brain iron accumulation and/or clinical features of pantothenate kinase-associated neurodegeneration (PMID: 12510040; Invitae). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 429585). This variant is also known as IVS2+3A‚ÜíG.