rs132630284

Positions:

• chrX-103787951-G-A
• chrX-103787951-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000533.5(PLP1):​c.607G>A​(p.Asp203Asn) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D203E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.60

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]

PLP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a disulfide_bond (size 44) in uniprot entity MYPR_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-103787951-G-A is Pathogenic according to our data. Variant chrX-103787951-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.607G>A	p.Asp203Asn	missense_variant	4/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.607G>A	p.Asp203Asn	missense_variant	4/7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2018

The D203N pathogenic variant in the PLP1 gene has been reported previously, using alternate nomenclature D202N, in a male with Pelizaeus-Merzbacher disease (Mimault et al., 1999). Functional studies show D203N is retained in the endoplasmic reticulum and forms fewer crosslinks between PLP and DM20, with the authors concluding that D203N disrupts the formation of a disulfide bridge in PLP/DM20 that is required for normal protein folding and trafficking (Dhaunchak and Nave, 2007; Dhaunchak et al., 2011). The D203N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D203N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. We interpret D203N as a pathogenic variant. -

Pelizaeus-Merzbacher disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 07, 2018

The PLP1 c.607G>A p.(Asp203Asn) missense variant , also known as p.(Asp202Asn), has been previously reported in one study where it was identified in one affected male with Pelizaeus-Merzbacher disease (PMD) (Mimault et al. 1999). Additionally, at least four other missense variants resulting in alternate amino acid changes at the 203 residue have been identified in individuals with PMD in the literature (Doll et al. 1992, Nagao et al. 1998, Mimault et al. 1999, Cailloux et al. 2000). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Expression of the p.(Asp203Asn) variant in various cell lines, including oli-neu, an oligodendrocyte cell line, revealed retention of the PLP1 protein in the endoplasmic reticulum (ER), which were rescued by cysteine to serine substitutions in the neighboring residues. It is postulated that p.(Asp203Asn) variant in the large extracellular loop 2 of the protein, induces minor structural changes that prevent efficient formation of normal disulfide bridges, which exposes unpaired cysteines in the oxidative environment of the ER and competing oxidations generate aberrant PLP dimers that fail to mature into oligomeric forms and are retained in the ER (Dhaunchak and Nave 2007, Dhaunchak et al. 2011). Based on the collective evidence, the c.607G>A p.(Asp203Asn) variant is classified as pathogenic for Pelizaeus-Merzbacher disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.74	T
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.88
MutPred		0.98		Gain of methylation at R205 (P = 0.0699);Gain of methylation at R205 (P = 0.0699);.;
MVP		0.99
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.65
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs132630284; hg19: chrX-103042880;