rs1553259643

Positions:

• chr1-161306718-GACAT-G

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.434_437del​(p.Tyr145SerfsTer16) 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: 29)
• Consequence: MPZ NM_000530.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.37

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 1-161306718-GACAT-G is Pathogenic according to our data. Variant chr1-161306718-GACAT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 531677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.434_437del	p.Tyr145SerfsTer16	frameshift_variant	3/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.434_437del	p.Tyr145SerfsTer16	frameshift_variant	3/6		NP_001302420.1
MPZ	XM_017001321.3	c.464_467del	p.Tyr155SerfsTer16	frameshift_variant	3/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.434_437del	p.Tyr145SerfsTer16	frameshift_variant	3/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 29

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

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2022

The c.434_437delATGT (p.Y145Sfs*16) alteration, located in exon 3 (coding exon 3) of the MPZ gene, consists of a deletion of 4 nucleotides from position 434 to 437, causing a translational frameshift with a predicted alternate stop codon after 16 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported once in a large cohort of patients with features of Charcot-Marie-Tooth disease (DiVincenzo, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

MPZ-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2022

The MPZ c.434_437delATGT variant is predicted to result in a frameshift and premature protein termination (p.Tyr145Serfs*16). This variant was reported in an individual with Charcot-Marie-Tooth disease (Supplemental Table 5, DiVincenzo et al. 2014. PubMed ID: 25614874). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MPZ are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 30, 2020

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2023

This sequence change creates a premature translational stop signal (p.Tyr145Serfs*16) 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 Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 531677). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease type 1B;C1843075:Charcot-Marie-Tooth disease dominant intermediate D;C1843153:Charcot-Marie-Tooth disease type 2J;C3888087:Charcot-Marie-Tooth disease type 2I Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 04-10-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553259643; hg19: chr1-161276508;