rs132630288

Positions:

• 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I187M) has been classified as Uncertain significance.

• 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]

RAB9B (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain 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/exons	MANE	UniProt
PLP1	NM_000533.5	c.560T>C	p.Ile187Thr	missense_variant	4/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.560T>C	p.Ile187Thr	missense_variant	4/7	1	NM_000533.5	P1

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PLP1 function (PMID: 23344956). 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. ClinVar contains an entry for this variant (Variation ID: 11085). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

Pelizaeus-Merzbacher disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Dec 15, 2021

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;.
MutationTaster	Benign	1.0	A;A;A
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;