rs879254109

Positions:

• chr1-161307301-AAGG-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000530.8(MPZ):​c.188_190del​(p.Ser63del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPZ NM_000530.8 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 5.82

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 13 ACMG points.

• PM1: In a strand (size 7) in uniprot entity MYP0_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000530.8. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-161307301-AAGG-A is Pathogenic according to our data. Variant chr1-161307301-AAGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 246121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161307301-AAGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.188_190del	p.Ser63del	inframe_deletion	2/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.188_190del	p.Ser63del	inframe_deletion	2/6		NP_001302420.1
MPZ	XM_017001321.3	c.218_220del	p.Ser73del	inframe_deletion	2/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.188_190del	p.Ser63del	inframe_deletion	2/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1993

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2021

Published functional studies demonstrate that in mice, S63del results in unfolded protein response including expression of CHOP and demyelinating neuropathy that mimics the corresponding human disease (Wrabetz et al., 2006, Pennuto et al., 2008); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 16495463, 23344956, 22734905, 29687021, 20461396, 26310628, 33879538, 34573256, 32973043, 7693130, 18255032) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

This variant, c.188_190del, results in the deletion of 1 amino acid(s) of the MPZ protein (p.Ser63del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Charcot-Marie-Tooth type 1B (CMT1B) (PMID: 7693130, 12402337, 22734905). It has also been observed to segregate with disease in related individuals. This variant is also known as Serine 34 del. ClinVar contains an entry for this variant (Variation ID: 246121). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MPZ function (PMID: 16495463, 18255032). For these reasons, this variant has been classified as Pathogenic. -

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)		0.0		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: rs879254109; hg19: chr1-161277091;