rs132630288

Variant names:

• chrX-103787904-T-C
• rs132630288
• NM_000533.5:c.560T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-103787904-T-C
• chrX-103787904-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000533.5(PLP1):​c.560T>C​(p.Ile187Thr) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ENSG00000288597 (HGNC:):

RAB9B (HGNC:14090): (RAB9B, member RAS oncogene family) This gene encodes a member of a subfamily of RAS small guanosine triphosphate (GTP)-binding proteins that regulate membrane trafficking. The encoded protein may be involved in endosome-to-Golgi transport. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Extracellular (size 55) in uniprot entity MYPR_HUMAN there are 19 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, 0.986
• PP5: Variant X-103787904-T-C is Pathogenic according to our data. Variant chrX-103787904-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.560T>C	p.Ile187Thr	missense_variant	Exon 4 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.560T>C	p.Ile187Thr	missense_variant	Exon 4 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:2

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PLP1 function (PMID: 23344956). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 187 of the PLP1 protein (p.Ile187Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PLP1-related conditions (PMID: 7522741, 19955111, 24139698). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11085). 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 not expected to disrupt PLP1 protein function. -

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pelizaeus-Merzbacher disease Pathogenic:1

Dec 15, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (c.560T>C, p.Ile187Thr) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 31110947, PMID 28286750, PMID 24575297, PMID 23344956, PMId 9427151, PMID 14745569). Variant prediction programs support a deleterious effect on the protein, although no functional studies have been published. The variant has been observed in affected male siblings and is carried by their mother. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.98	D;D;P
Vest4		0.87
MutPred		0.93		Gain of disorder (P = 0.007);Gain of disorder (P = 0.007);.;
MVP		1.0
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs132630288; hg19: chrX-103042833;