rs1553259683

Variant names:

• chr1-161306858-G-A
• rs1553259683
• NM_000530.8:c.298C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000530.8(MPZ):​c.298C>T​(p.Gln100*) variant causes a stop gained change involving the alteration of a non-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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MPZ NM_000530.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.29

Genes affected

MPZ (HGNC:7225): (myelin protein zero) This gene is specifically expressed in Schwann cells of the peripheral nervous system and encodes a type I transmembrane glycoprotein that is a major structural protein of the peripheral myelin sheath. The encoded protein contains a large hydrophobic extracellular domain and a smaller basic intracellular domain, which are essential for the formation and stabilization of the multilamellar structure of the compact myelin. Mutations in this gene are associated with autosomal dominant form of Charcot-Marie-Tooth disease type 1 (CMT1B) and other polyneuropathies, such as Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN). A recent study showed that two isoforms are produced from the same mRNA by use of alternative in-frame translation termination codons via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 1-161306858-G-A is Pathogenic according to our data. Variant chr1-161306858-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 531678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161306858-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8	c.298C>T	p.Gln100*	stop_gained	Exon 3 of 6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.298C>T	p.Gln100*	stop_gained	Exon 3 of 6		NP_001302420.1
MPZ	XM_017001321.3	c.328C>T	p.Gln110*	stop_gained	Exon 3 of 6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.298C>T	p.Gln100*	stop_gained	Exon 3 of 6	1	NM_000530.8	ENSP00000432943.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease, type I Pathogenic:1

Dec 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln100*) in the MPZ gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with Charcot-Marie-Tooth disease (CMT) (PMID: 19259128). Loss-of-function variants in MPZ are known to be pathogenic (PMID: 14711881). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Benign	0.73	D
Vest4		0.82
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1553259683; hg19: chr1-161276648;