ClinVar Miner

Submissions for variant NM_000533.5(PLP1):c.453G>A (p.Lys151=)

dbSNP: rs886044450
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000380260 SCV000344984 pathogenic not provided 2016-09-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000691268 SCV000819020 pathogenic Hereditary spastic paraplegia 2 2018-04-13 criteria provided, single submitter clinical testing Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant results in an aberrant transcript encoding a PLP1 with an in-frame 14-amino acid deletion within the PLP1-specific domain (PMID: 16287154). For these reasons, this variant has been classified as Pathogenic. Two different variants affecting this nucleotide (c.453G>T, c.453G>C) have been determined to be pathogenic (PMID: 7531827, 12601703, 16287154, 28366443). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. This variant has been reported in individuals affected with Pelizaeus-Merzbacher disease (PMD) (PMID: 12601703, 16287154). This variant is also known as G450A in the literature. ClinVar contains an entry for this variant (Variation ID: 290425). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 151 of the PLP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PLP1 protein. This variant also falls at the last nucleotide of exon 3 of the PLP1 coding sequence, which is part of the consensus splice site for this exon.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV004595503 SCV005088466 likely pathogenic Pelizaeus-Merzbacher disease 2021-12-10 criteria provided, single submitter clinical testing This variant (c.453G>A, p.Lys151=) is the last nucleotide af exon 3 and predicts a synonymous change. It has not been observed in population databases (gnomAD). It has been described in the literature, and functional studies indicate a deleterious effect on protein expression (PMID 16287154, PMID 30195779).

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