Submissions for variant NM_024411.5(PDYN):c.-19-1G>C

gnomAD frequency: 0.00003  dbSNP: rs769835663

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779344	SCV000915937	uncertain significance	Spinocerebellar ataxia type 23	2018-08-20	criteria provided, single submitter	clinical testing	The PDYN c.-19-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The c.-19-1G>C variant is reported at a frequency of 0.000097 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, the c.-19-1G>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal dominant spinocerebellar ataxia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323721	SCV004029704	uncertain significance	not specified	2023-07-11	criteria provided, single submitter	clinical testing	Variant summary: PDYN c.-19-1G>C is located in the 5'UTR of the PDYN gene, in a canonical splice-site and is predicted to affect mRNA splicing, potentially resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and creates/strengthens a cryptic 3' acceptor site that is also located in the 5'UTR upstream of the ATG start codon. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.3e-05 in 247982 control chromosomes (gnomAD). c.-19-1G>C has been reported in the literature at least once in a cohort of individuals affected with cerebellar ataxia undergoing multigene panel testing (Ghorbani_2022). This report does not provide unequivocal conclusions about association of the variant with Spinocerebellar Ataxia Type 23. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35401678). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.