NM_000533.5:c.409C>T

Variant names:

• chrX-103786682-C-T
• rs132630295
• NM_000533.5:c.409C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000533.5(PLP1):​c.409C>T​(p.Arg137Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,417 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.42
• Publications: 20 publications found

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000533.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-103786682-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2230585.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 2, Pelizeaus-Merzbacher spectrum disorder, Pelizaeus-Merzbacher disease in female carriers, null syndrome, Pelizaeus-Merzbacher disease, transitional form, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease, connatal form.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant X-103786682-C-T is Pathogenic according to our data. Variant chrX-103786682-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11098.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.409C>T	p.Arg137Trp	missense_variant	Exon 3 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.409C>T	p.Arg137Trp	missense_variant	Exon 3 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097417 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362785

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841378

Other (OTH) AF: 0.00 AC: 0 AN: 46071

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

Alfa AF: 0.000131 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1 Uncertain:1

Apr 17, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 137 of the PLP1 protein (p.Arg137Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with complicated spastic paraplegia and/or Pelizaeus-Merzbacher disease (PMID: 17438221, 24139698). ClinVar contains an entry for this variant (Variation ID: 11098). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PLP1 function (PMID: 30314286). This variant disrupts the p.Arg137 amino acid residue in PLP1. Other variant(s) that disrupt this residue have been observed in individuals with PLP1-related conditions (PMID: 24139698), which suggests that this may be a clinically significant amino acid residue. 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. -

Pelizaeus-Merzbacher disease Pathogenic:1

Nov 22, 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.409G>T, p.Arg137Trp) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 17438221, PMID 24139698). This nucleotide resides in a region involved in splice site regulation (PMID 16288477), and variant prediction programs suggest a deleterious effect on the PLP1 protein, although no functional studies have been published. It has been found in 2 affected males in a family, related through maternal lines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;L
PhyloP100		2.4
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.54
MutPred		0.66		Loss of disorder (P = 0.0182);Loss of disorder (P = 0.0182);
MVP		1.0
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.93
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs132630295; hg19: chrX-103041611; COSMIC: COSV58277298; COSMIC: COSV58277298;