rs755446743

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4_SupportingPP5BS2

The NM_000530.8(MPZ):c.706_708delAAG(p.Lys236del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000217 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K236K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MPZ
NM_000530.8 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:2O:1

Conservation

PhyloP100: 5.69

Publications

5 publications found

Variant links:

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]

MPZ Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
neuropathy, congenital hypomyelinating, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease dominant intermediate D
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2J
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MPZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000530.8. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-161305914-CCTT-C is Pathogenic according to our data. Variant chr1-161305914-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447734.

BS2

High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8 link	c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6	ENST00000533357.5	NP_000521.2	P25189-1
MPZ	NM_001315491.2 link	c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6		NP_001302420.1	P25189A0A5F9ZI26
MPZ	XM_017001321.3 link	c.675+191_675+193delAAG		intron_variant	Intron 5 of 5		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5 link	c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6	1	NM_000530.8	ENSP00000432943.1		P25189-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000360

AC:

AN:

249906

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461562

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111946

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on MPZ protein properties in vitro (Raasakka et al., 2019).; In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12207932, 15716547, 26310628, 20800346, 28364294, 21336783, 29687021, 31173589, 33179255, 32376792, 20461396, 33359733) -

Apr 13, 2017

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PM1, PM2, PS3_supporting, PS4_supporting -

Charcot-Marie-Tooth disease

Pathogenic:2Uncertain:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Lys236del (historically referred to as K207del or K263Del) variant in MPZ has been reported in 4 individuals with late-onset Charcot-Marie-Tooth disease and segregated with disease in two relatives (Street 2002 PubMed: 12207932, Volodarsky 2021 PubMed: 32376792; Sowden 2005 PMID: 15716547). This variant is an in-frame 1-amino acid deletion. It has also been reported by other clinical laboratories in ClinVar (Variation ID 447734) and detected in 1/64552 non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://exac.broadinstitute.org). Functional data demonstrates that this variant affects protein function (Bai 2018 PubMed: 29687021). In summary, this variant is likely pathogenic for Charcot-Marie-Tooth disease in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PM4_Supporting, PS3_Moderate, PP1. -

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dejerine-Sottas disease

Pathogenic:1

Apr 10, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a three nucleotide deletion (delAAG) at positions 706_708 of the coding MPZ gene and results in the deletion of the Lys236 codon. The 236 residue falls in the cytoplasmic tail which contributes to the physical properties of the myelin lipid membrane (PMID: 31173589). This is a previously reported variant (ClinVar 447734) that has been observed in individuals affected by Charcot–Marie–Tooth disease (PMID: 32376792, 33179255, 26310628, 36203352) and has been found to segregate with this disorder in two families (PMID: 12207932, 12207932). This variant is present in 35 of 1,613,628 alleles (0.002%) in the gnomAD v4.0.0 population dataset. Predictions from bioinformatic tools are inconclusive for this variant, and the Lys236 residue at this position is conserved across the vertebrate species examined. In vitro analysis indicates that this variant significantly disrupts the lipid membrane structure of myelin (PMID: 31173589). Based upon the evidence, we consider this a pathogenic variant. ACMG Criteria: PM2, PM4, PS3, PS4 -

Charcot-Marie-Tooth disease, type I

Pathogenic:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.706_708del, results in the deletion of 1 amino acid(s) of the MPZ protein (p.Lys236del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755446743, gnomAD 0.006%). This variant has been observed in individuals with late-onset Charcot-Marie-Tooth disease (PMID: 12207932, 15716547). It has also been observed to segregate with disease in related individuals. This variant is also known as K263Del. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MPZ function (PMID: 29687021, 31173589). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease type 2I

Pathogenic:1

Oct 06, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.706_708delAAG (p.K236del) alteration is located in exon 6 (coding exon 6) of the MPZ gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.706 and c.708, resulting in the deletion of the lysine residue at codon 236. This alteration has been previously reported in multiple families with features of autosomal dominant, adult onset Charcot-Marie-Tooth disease; however, the phenotype reported in one family shows variable penetrance with symptoms ranging from being asymptomatic to having foot deformities, pedal numbness, and muscle cramps (Street, 2002; Sowden, 2005; Volodarsky, 2021). This amino acid position is highly conserved in available vertebrate species. Overall, functional studies suggest that the protein is mislocalized to the cytoplasm, alters protein-lipid interactions, and activates the unfolded protein response in vitro; however, additional evidence is needed to confirm these results (Bai, 2018; Raasakka, 2019). This alteration is predicted to be neutral by in silico analysis (Choi, 2012). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dejerine-Sottas disease;C0270912:Charcot-Marie-Tooth disease type 1B;C0393818:Congenital hypomyelinating neuropathy;C1843153:Charcot-Marie-Tooth disease type 2J

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpretted as Uncertain significance and reported on 07/27/2018 by GTR ID 26957. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=42/58

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over