Submissions for variant NM_000533.5(PLP1):c.4+1del

dbSNP: rs1602373055

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810065	SCV000950252	pathogenic	Hereditary spastic paraplegia 2	2018-08-30	criteria provided, single submitter	clinical testing	Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PLP1 are known to be pathogenic (PMID: 18470932). Experimental evidence shows this variant results in a altered mRNA product that encodes a null allele (PMID: 9247276). This variant has been observed to segregate with progressive, demyelinating peripheral neuropathy in a family (PMID: 9247276). This variant is also known as G-4 deletion. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 1 of the PLP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV004595533	SCV005088451	pathogenic	Pelizaeus-Merzbacher disease	2021-11-22	criteria provided, single submitter	clinical testing	This intronic variant (c.4+1delG) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 9247276, PMID 18470932). The variant has been shown to segregate with disease in a large family, and studies indicate the deletion produces a null PLP1 allele with no protein expression.