rs1556267123

Positions:

• chrX-103786626-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000621218.5(PLP1):​c.354_355del​(p.Gly120ProfsTer83) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 ENST00000621218.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.29

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103786626-CAG-C is Pathogenic according to our data. Variant chrX-103786626-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-103786626-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.354_355del	p.Gly120ProfsTer83	frameshift_variant	3/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.354_355del	p.Gly120ProfsTer83	frameshift_variant	3/7	1	NM_000533.5	ENSP00000484450	P1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pelizaeus-Merzbacher disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Nov 15, 2021	This variant (c.354_355delAG, p.Gly120Profs*83) results in a frameshift to a premature termination. It has not been observed in population databases (gnomAD), but it has been described in the literature (PMID 20022439, PMID 33450882). No functional studies have been published. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2021	- -

Hereditary spastic paraplegia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 520586). This variant is also known as c.352_353delAG (p.Gly130fs). This premature translational stop signal has been observed in individual(s) with PLP1-related conditions (PMID: 20022439, 26795593). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly120Profs*83) in the PLP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLP1 are known to be pathogenic (PMID: 18470932). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2014

The c.354_355del () alteration, located in exon 3 (coding exon 3) of the PLP1 gene, consists of a deletion of 2 nucleotides from position 354 to 355, causing a translational frameshift with a predicted alternate stop codon after amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). The alteration has been observed in affected individuals: _x000D_ This frameshift alteration was previously reported in a 26-year old Japanese man with a mild form of PMD (Osaka, 2009). He had some motor and speech delays and lower limb spasticity in childhood, however he could speak meaningful words and walk independently until age 15. He subsequently developed signs of mental regression at age 20 and developed seizures. Upon evaluation at age 24 he also had oculomotor apraxia (but no nystagmus), hypertonia, and incomplete brain myelination on T2 imaging. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ PLP1 alterations affecting exon 3B cause the mildest form of PMD (form 4). Exon 3B is spliced out during messenger RNA production of DM20 and therefore the expression and function of that isoform protein are preserved. The mutant PLP1 protein is much shorter than the wild type and is expected to be degraded via nonsense-mediated decay. The combination of preserved DM20 and lack of mutant PLP1 proteins is what is predicted to result in the mild phenotype ()Osaka, 2010). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33450882, 20022439, 26795593) -

Computational scores

Source: dbNSFP v4.3

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: rs1556267123; hg19: chrX-103041555;