chrX-103787951-G-A

Variant names:

• chrX-103787951-G-A
• rs132630284
• NM_000533.5:c.607G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 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 (★★). ClinVar reports functional evidence for this variant: "SCV000322289: 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" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D203Y) has been classified as Uncertain significance.

• 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
• Publications: 7 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322289: 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).; SCV004801490: 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).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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-103787951-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11081.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 Pelizeaus-Merzbacher spectrum disorder, null syndrome, hereditary spastic paraplegia 2, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease in female carriers, Pelizaeus-Merzbacher disease, connatal form, Pelizaeus-Merzbacher disease, transitional form.
• 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 VariationId is 265417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000533.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	NM_000533.5	MANE Select	c.607G>A	p.Asp203Asn	missense	Exon 4 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.607G>A	p.Asp203Asn	missense	Exon 5 of 8	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.502G>A	p.Asp168Asn	missense	Exon 4 of 7	NP_955772.1	P60201-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.607G>A	p.Asp203Asn	missense	Exon 4 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.502G>A	p.Asp168Asn	missense	Exon 4 of 7	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.649G>A	p.Asp217Asn	missense	Exon 5 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Pelizaeus-Merzbacher disease (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.6
PrimateAI	Uncertain	0.74	T
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.98		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
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs132630284; hg19: chrX-103042880;