rs1060500909

Variant names:

• chrX-103785717-T-C
• rs1060500909
• NM_000533.5:c.140T>C

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.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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 26) in uniprot entity MYPR_HUMAN there are 6 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, 0.964
• 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 rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.140T>C	p.Ile47Thr	missense_variant	Exon 2 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.140T>C	p.Ile47Thr	missense_variant	Exon 2 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pelizaeus-Merzbacher disease Pathogenic:2

Sep 23, 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.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). -

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3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary spastic paraplegia 2 Pathogenic:1

Oct 03, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 06, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;D;D;D;D;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;M;.;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D;.;D;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;.;D;D;D;.;D;.;.
Sift4G	Uncertain	0.0050	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		0.83		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		0.99
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.87
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: rs1060500909; hg19: chrX-103040646;