rs1556267123
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000533.5(PLP1):c.354_355delAG(p.Gly120ProfsTer83) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000533.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Pelizaeus-Merzbacher disease Pathogenic:2
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This variant (c.354_355delAG, p.Gly120Profs*83) results in a frameshift to a premature termination. It has not been observed in population databases (gnomAD), but it has been described in the literature (PMID 20022439, PMID 33450882). No functional studies have been published. -
Hereditary spastic paraplegia 2 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gly120Profs*83) in the PLP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLP1 are known to be pathogenic (PMID: 18470932). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PLP1-related conditions (PMID: 20022439, 26795593). This variant is also known as c.352_353delAG (p.Gly130fs). ClinVar contains an entry for this variant (Variation ID: 520586). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.354_355del () alteration, located in exon 3 (coding exon 3) of the PLP1 gene, consists of a deletion of 2 nucleotides from position 354 to 355, causing a translational frameshift with a predicted alternate stop codon after amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). The alteration has been observed in affected individuals: _x000D_ This frameshift alteration was previously reported in a 26-year old Japanese man with a mild form of PMD (Osaka, 2009). He had some motor and speech delays and lower limb spasticity in childhood, however he could speak meaningful words and walk independently until age 15. He subsequently developed signs of mental regression at age 20 and developed seizures. Upon evaluation at age 24 he also had oculomotor apraxia (but no nystagmus), hypertonia, and incomplete brain myelination on T2 imaging. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ PLP1 alterations affecting exon 3B cause the mildest form of PMD (form 4). Exon 3B is spliced out during messenger RNA production of DM20 and therefore the expression and function of that isoform protein are preserved. The mutant PLP1 protein is much shorter than the wild type and is expected to be degraded via nonsense-mediated decay. The combination of preserved DM20 and lack of mutant PLP1 proteins is what is predicted to result in the mild phenotype ()Osaka, 2010). Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33450882, 20022439, 26795593) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at