rs281865125

Positions:

• chr1-161306849-CT-C

Variant summary

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

The NM_000530.8(MPZ):​c.306del​(p.Asp104ThrfsTer14) variant causes a frameshift change involving the alteration of a non-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: 29)
• Consequence: MPZ NM_000530.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:2
• Conservation: PhyloP100: 0.0250

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 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 1-161306849-CT-C is Pathogenic according to our data. Variant chr1-161306849-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306849-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.306del	p.Asp104ThrfsTer14	frameshift_variant	3/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.306del	p.Asp104ThrfsTer14	frameshift_variant	3/6		NP_001302420.1
MPZ	XM_017001321.3	c.336del	p.Asp114ThrfsTer14	frameshift_variant	3/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.306del	p.Asp104ThrfsTer14	frameshift_variant	3/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1B Other:2

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Charcot-Marie-Tooth disease dominant intermediate D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 16, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Asp104Thrfs*14) in the MPZ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPZ are known to be pathogenic (PMID: 14711881). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with MPZ-related conditions (PMID: 8816708). ClinVar contains an entry for this variant (Variation ID: 41019). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive Dejerine-Sottas syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1996

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs281865125; hg19: chr1-161276639;