NM_000533.5:c.701A>T

Variant names:

• chrX-103789337-A-T
• rs1060500908
• NM_000533.5:c.701A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000533.5(PLP1):​c.701A>T​(p.Gln234Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q234P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Myelin proteolipid protein (size 275) in uniprot entity MYPR_HUMAN there are 52 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.701A>T	p.Gln234Leu	missense_variant	Exon 6 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.701A>T	p.Gln234Leu	missense_variant	Exon 6 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 2 Uncertain:1

Nov 26, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with leucine at codon 234 of the PLP1 protein (p.Gln234Leu). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PLP1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Gln234Pro, also known as p.Gln233Pro) has been reported in an individual affected with Pelizaeus-Merzbacher disease (PMID: 10417279). The clinical significance of this variant is not known. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.93	D;D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.41	B;B;B
Vest4		0.42
MutPred		0.72		Loss of catalytic residue at Q234 (P = 0.001);Loss of catalytic residue at Q234 (P = 0.001);.;
MVP		0.98
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.30
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060500908; hg19: chrX-103044266;