rs281865128

Positions:

• chr1-161306426-C-G
• chr1-161306426-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000533357.5(MPZ):​c.487G>C​(p.Gly163Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G163A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MPZ ENST00000533357.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:2 O:1
• Conservation: PhyloP100: 4.01

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.

• PS1: Transcript ENST00000533357.5 (MPZ) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 208148
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000533357.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 1-161306426-C-G is Pathogenic according to our data. Variant chr1-161306426-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306426-C-G is described in Lovd as [Pathogenic]. Variant chr1-161306426-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.487G>C	p.Gly163Arg	missense_variant	4/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.487G>C	p.Gly163Arg	missense_variant	4/6		NP_001302420.1
MPZ	XM_017001321.3	c.517G>C	p.Gly173Arg	missense_variant	4/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.487G>C	p.Gly163Arg	missense_variant	4/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2023	This variant segregates with CMT in multiple families. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. One other missense variant at this codon produces the same amino acid change as this variant (c.487G>A; p.Gly163Arg) and is also considered to be pathogenic. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been referred to as both p.Gly134Arg and p.Gly173Arg in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant (referred to as G134R) impairs protein oligomerization, thus impairing protein function (PMID: 17915947). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 20, 2023	PP1_strong, PP3, PM2_moderate, PS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2022	Published functional studies demonstrate that G163R (referred to as G134R due to alternative nomenclature) causes a loss of dimerization and oligomerization ability, thus impairing protein function (Plotkowski et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 14711881, 26135405, 15170620, 34232518, 27614573, 12207932, 16414078, 18611372, 17915947, 30920665, 20461396, 26310628, 33179255, 33359733) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 03, 2020	PS3, PS4 -

Charcot-Marie-Tooth disease Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2022

The c.487G>C (p.G163R) alteration is located in exon 4 (coding exon 4) of the MPZ gene. This alteration results from a G to C substitution at nucleotide position 487, causing the glycine (G) at amino acid position 163 to be replaced by an arginine (R). This variant has been shown to segregate with Charcot-Marie-Tooth (CMT) disease in multiple families (Eggers, 2004; van Doormaal, 2016; Street, 2002). It has also been identified in a cohort of kindred descended from a single common ancestor (Caress, 2019). A different nucleotide substitution (c.487G>A) that results in the same amino acid change (p.G163R) has been reported in association with CMT (Nelis, 1996; Numakura, 2002; Werheid, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 163 of the MPZ protein (p.Gly163Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth type 1 (CMT1) (PMID: 12207932, 15170620). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MPZ protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.68		Gain of methylation at G163 (P = 0.0575);
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.61
gMVP		0.98

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: rs281865128; hg19: chr1-161276216;