rs1553259511

Positions:

• chr1-161305976-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000530.8(MPZ):​c.646_647insA​(p.Thr216AsnfsTer19) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MPZ NM_000530.8 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.40

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161305976-G-GT is Pathogenic according to our data. Variant chr1-161305976-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 462798.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.646_647insA	p.Thr216AsnfsTer19	frameshift_variant, splice_region_variant	6/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.646_647insA	p.Thr216AsnfsTer19	frameshift_variant, splice_region_variant	6/6		NP_001302420.1
MPZ	XM_017001321.3	c.675+131_675+132insA		intron_variant			XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.646_647insA	p.Thr216AsnfsTer19	frameshift_variant, splice_region_variant	6/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.646dupA (p.T216Nfs*19) alteration, located in exon 6 (coding exon 6) of the MPZ gene, consists of a duplication of A at position 646, causing a translational frameshift with a predicted alternate stop codon after 19 amino acids. This alteration occurs at the 3' terminus of the MPZ gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data)._x000D_ _x000D_ _x000D_ _x000D_ for autosomal dominant MPZ-related Charcot-Marie-Tooth disease type 1 and autosomal recessive MPZ-related Dejerine-Sottas disease; however, its classification for autosomal dominant MPZ-related neuropathic disorders is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in at least one individual with clinical features of Charcot-Marie-Tooth disease (Sanmaneechai, 2015). Based on internal structural analysis, this variant results in loss of Ser233, phosphorylation of which is necessary for P0 adhesion function, and loss of a PKC substrate motif (RSTK) (Gaboreanu, 2007; Hilmi, 1995; Xu, 2001). Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr216Asnfs*19) in the MPZ gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the MPZ protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MPZ protein in which other variant(s) (p.Glu222Valfs*14) have been determined to be pathogenic (PMID: 7530550). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 462798). This premature translational stop signal has been observed in individuals with Charcot Marie Tooth disease (PMID: 26310628). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553259511; hg19: chr1-161275766;