rs132630283
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_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 (★).
Frequency
Genomes: not found (cov: 23)
Consequence
PLP1
NM_000533.5 missense
NM_000533.5 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 7.63
Genes affected
PLP1 (HGNC:9086): (proteolipid protein 1) This gene encodes a transmembrane proteolipid protein that is the predominant component of myelin. The encoded protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations in this gene cause Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Alternatively splicing results in multiple transcript variants, including the DM20 splice variant. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a disulfide_bond (size 44) in uniprot entity MYPR_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000533.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLP1 | NM_000533.5 | c.671T>C | p.Leu224Pro | missense_variant | 5/7 | ENST00000621218.5 | NP_000524.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLP1 | ENST00000621218.5 | c.671T>C | p.Leu224Pro | missense_variant | 5/7 | 1 | NM_000533.5 | ENSP00000484450.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
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 | Labcorp Genetics (formerly Invitae), Labcorp | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at