rs132630281

Positions:

• chrX-103788469-G-T

Variant summary

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

The ENST00000621218.5(PLP1):​c.655G>T​(p.Val219Phe) 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. V219G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 ENST00000621218.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.55

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 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000621218.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-103788470-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3255445.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-103788469-G-T is Pathogenic according to our data. Variant chrX-103788469-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11077.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.655G>T	p.Val219Phe	missense_variant	5/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.655G>T	p.Val219Phe	missense_variant	5/7	1	NM_000533.5	ENSP00000484450	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pelizaeus-Merzbacher disease Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Dec 27, 2021	This missense variant (c.655G>T, p.Val219Phe) has not been observed in population databases (gnomAD). It has been described in the literature and reported to segregate with affected males in a 4 generation family (PMID 1715570). Variant prediction programs support a deleterious effect on the protein, although no functional studies have been published. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 2 (SP2) (MIM#312920). Gain of function has been speculated to be the mechanism of disease for missense variants that are associated with Pelizaeus-Merzbacher disease (PMD) (MIM#312080) (PMID: 28286750). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. PMD and SP2 are at different ends of the same clinical spectrum, and are known to have variable phenotypes. Heterozygous females are generally either unaffected or only mildly affected compared to male family members with the same variant (OMIM, PMID: 16778599). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myelin proteolipid protein domain. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the literature in multiple individuals from one family with PMD (PMID:1715570) and in one other unrelated individual with PMD (PMID:24139698). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with disease in one family (PMID:1715570). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1991	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.97	D;D;P
Vest4		0.92
MutPred		0.87		Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;
MVP		1.0
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.68
gMVP		0.99

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: rs132630281; hg19: chrX-103043398;