rs864622194

chrX-103776997-T-CchrX-103776997-T-G

Variant summary

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

The NM_000533.5(PLP1):c.2T>C(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 NM_000533.5 start_lost, splice_region
• Scores: Splicing: ADA: 0.001673
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.55

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.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103776997-T-C is Pathogenic according to our data. Variant chrX-103776997-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 219649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLP1	NM_000533.5	c.2T>C	p.Met1?	start_lost, splice_region_variant	1/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.2T>C	p.Met1?	start_lost, splice_region_variant	1/7	1	NM_000533.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2015

This sequence change affects the initiator methionine of the PLP1 mRNA. This variant has been reported in the literature and is not present in population databases. This variant was reported in 2 individuals affected with Pelizaeus-Merzbacher disease. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 10417279, 18470932). Different mutations in the initiator codon (p.Met1Val, p.Met1Ile, p.Met1Arg) have been reported in patients affected with Pelizaeus-Merzbacher disease (PMID: 12910435, 8786077, 22343157), indicating that this residue may be critical for protein function. An experimental study using RT-PCR from one patient's fibroblasts has shown that this missense change causes loss of transcript (PMID: 18470932). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2020

The c.2T>C (p.M1?) alteration is located in coding exon 1 of the PLP1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on data from the Genome Aggregation Database (gnomAD), the PLP1 c.2T>C alteration was not observed, with coverage at this position. This alteration was previously reported in a patient with sporadic Pelizaeus-Merzbacher Disease (Mimault, 1999). Other alterations affecting the initiation codon, c.1A>G, c.2T>G, and c.3G>A, were described in families affected with hereditary spastic paraplegia or PMD (Hand, 2012; Hebbar, 2018; Plecko, 2003). The p.M1 amino acid is conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.73
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T;T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-2.1	N;.;N;N;N;.;N;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;.;D;D;D;.;D;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		0.12, 0.0090	.;.;.;.;.;B;.;B;B
Vest4		0.87, 0.87, 0.80
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);Gain of catalytic residue at M1 (P = 0.0067);
MVP		1.0
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.024
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: rs864622194; hg19: chrX-103031925;