1-161306722-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_000530.8(MPZ):c.434A>C(p.Tyr145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y145C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MPZ
NM_000530.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.74

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000530.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-161306722-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430459.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.

PP5

Variant 1-161306722-T-G is Pathogenic according to our data. Variant chr1-161306722-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 14191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306722-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8 link	c.434A>C	p.Tyr145Ser	missense_variant	Exon 3 of 6	ENST00000533357.5	NP_000521.2	P25189-1
MPZ	NM_001315491.2 link	c.434A>C	p.Tyr145Ser	missense_variant	Exon 3 of 6		NP_001302420.1	P25189A0A5F9ZI26
MPZ	XM_017001321.3 link	c.464A>C	p.Tyr155Ser	missense_variant	Exon 3 of 6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5 link	c.434A>C	p.Tyr145Ser	missense_variant	Exon 3 of 6	1	NM_000530.8	ENSP00000432943.1		P25189-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251494

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the variant alters normal MPZ function (PMID: 29687021); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in a family with peripheral neuropathy and deafness (PMID: 12805115); This variant is associated with the following publications: (PMID: 30677751, 12845552, 26310628, 20461396, 29687021, 12805115) -

Aug 05, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in abnormal protein function by causing protein to be retained in the endoplasmic reticulum (ER) rather than being transported to the cell membrane or myelin sheath (PMID 29687021). The variant is located in a region that is considered important for protein function and/or structure. -

Dejerine-Sottas disease;C0205713:Roussy-Lévy syndrome;C0270912: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;C4721436:Charcot-Marie-Tooth disease type 4E

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 1B

Pathogenic:1

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MPZ-related disorder

Pathogenic:1

Mar 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MPZ c.434A>C variant is predicted to result in the amino acid substitution p.Tyr145Ser. This variant has been reported in multiple individuals with autosomal dominant Charcot-Marie-Tooth disease (Leal et al 2003. PubMed ID: 12845552; Starr et al. 2003. PubMed ID: 12805115; Taniguchi T et al 2020. PubMed ID: 33179255). An in vitro experimental study suggests this variant impacts protein localization leading to increased endoplasmic reticulum retention (Bai et al. 2018. PubMed ID: 29687021). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and is reported in ClinVar as pathogenic by several outside laboratories (http://gnomad.broadinstitute.org/variant/1-161276512-T-G; https://www.ncbi.nlm.nih.gov/clinvar/variation/14191/). Given the evidence, this variant is interpreted as pathogenic. -

Charcot-Marie-Tooth disease, type I

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 145 of the MPZ protein (p.Tyr145Ser). This variant is present in population databases (rs121913603, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary peripheral neuropathy and hereditary sensory motor neuropathy with deafness (PMID: 12805115, 12845552). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MPZ variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 11,906 individuals referred to our laboratory for MPZ testing. ClinVar contains an entry for this variant (Variation ID: 14191). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MPZ protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-0.16

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

REVEL

Benign

0.24

Sift

Benign

0.085

Sift4G

Benign

0.39

Polyphen

0.40

Vest4

0.88

MutPred

0.51

Gain of disorder (P = 0.1);

MVP

0.97

MPC

0.86

ClinPred

0.18

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -16

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over