rs1060500909
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000533.5(PLP1):c.140T>C(p.Ile47Thr) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
PLP1
NM_000533.5 missense
NM_000533.5 missense
Scores
8
7
1
Clinical Significance
Conservation
PhyloP100: 7.67
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 Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000533.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
?
Variant X-103785717-T-C is Pathogenic according to our data. Variant chrX-103785717-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLP1 | NM_000533.5 | c.140T>C | p.Ile47Thr | missense_variant | 2/7 | ENST00000621218.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLP1 | ENST00000621218.5 | c.140T>C | p.Ile47Thr | missense_variant | 2/7 | 1 | NM_000533.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pelizaeus-Merzbacher disease Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The missense variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.91). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000405941/PMID: 24519770). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Sep 23, 2021 | This missense variant (c.140T>C, p.Ile47Thr) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 24519770, PMID 27179222, PMID 30104812). Variant prediction programs suggest a deleterious effect on the PLP1 protein, but no functional studies have been published. The variant has been shown to segregate with the disease (PMID 24519770, 27179222). - |
Hereditary spastic paraplegia 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2016 | In summary, this variant is a rare missense that segregates with disease in a single family and is predicted to affect protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to segregate with Pelizaeus-Merzbacher disease (PMD) in a single family (PMID: 24519770). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 47 of the PLP1 protein (p.Ile47Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. - |
Pelizaeus-Merzbacher disease;C1839264:Hereditary spastic paraplegia 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 06, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D;D;D;D;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;D;.;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;D;.;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
0.95, 0.98, 0.71
.;P;P;.;.;D;.;D;P
Vest4
0.90, 0.72
MutPred
Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);
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