rs132630283
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000533.5(PLP1):c.671T>C(p.Leu224Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L224F) has been classified as Pathogenic.
Frequency
Consequence
NM_000533.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLP1 | NM_000533.5 | c.671T>C | p.Leu224Pro | missense_variant | 5/7 | ENST00000621218.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLP1 | ENST00000621218.5 | c.671T>C | p.Leu224Pro | missense_variant | 5/7 | 1 | NM_000533.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Pelizaeus-Merzbacher disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1992 | - - |
Hereditary spastic paraplegia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2023 | This variant is also known as p.Leu223Pro. This missense change has been observed in individual(s) with Pelizaeus-Merzbacher diseae (PMID: 1384324). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 224 of the PLP1 protein (p.Leu224Pro). 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. This variant disrupts the p.Leu224 amino acid residue in PLP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23347225, 26786043; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PLP1 function (PMID: 22016529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLP1 protein function. ClinVar contains an entry for this variant (Variation ID: 11080). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at