Submissions for variant NM_000533.5(PLP1):c.762+5G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV005052413	SCV005685641	likely pathogenic	not provided	2024-07-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: Fang2022[Abstract], 23347225)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005105385	SCV005841044	uncertain significance	Hereditary spastic paraplegia 2	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the PLP1 gene. It does not directly change the encoded amino acid sequence of the PLP1 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 individual(s) with PLP null syndrome (PMID: 23347225). 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. 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.