1-161306863-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000530.8(MPZ):c.293G>A(p.Arg98His) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,962 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R98L) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.17

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.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161306864-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-161306863-C-T is Pathogenic according to our data. Variant chr1-161306863-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306863-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.293G>A	p.Arg98His	missense_variant	3/6	ENST00000533357.5
MPZ	NM_001315491.2	c.293G>A	p.Arg98His	missense_variant	3/6
MPZ	XM_017001321.3	c.323G>A	p.Arg108His	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.293G>A	p.Arg98His	missense_variant	3/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 29

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

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74222

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

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	Oct 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 12, 2015	Not found in the total gnomAD dataset, and the data is high quality. Found in multiple individuals with expected phenotype for this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregates with disease in multiple families -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 20, 2022	PM1, PM2, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2022	Published functional studies demonstrate a damaging effect on cell adhesiveness (Lee et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31211173, 33179255, 31372974, 12221176, 8797476, 7688964, 10737979, 20215982, 10581375, 11437164, 29687021, 32376792, 33726816, 20461396, 8644725, 26310628) -

Charcot-Marie-Tooth disease type 1B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000014176) and different missense changes at the same codon (p.Arg98Cys, p.Arg98Leu, p.Arg98Pro / ClinVar ID: VCV000014174, VCV000014175, VCV000586152) Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2002	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2020

The p.R98H pathogenic mutation (also known as c.293G>A), located in coding exon 3 of the MPZ gene, results from a G to A substitution at nucleotide position 293. The arginine at codon 98 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with demyelinating Charcot-Marie Tooth disease and to co-segregate with disease in multiple families (Lagueny A et al. Neuromuscul. Disord., 1999 Oct;9:361-7; Ohnishi A et al. J. Neurol. Sci., 1999 Dec;171:97-109; Rouger H et al. Am. J. Hum. Genet., 1996 Mar;58:638-41). Additionally, in vitro functional studies have shown that protein with this alteration fails to localize to the cell membrane and increases the unfolded protein response in the cell (Bai Y et al. Ann Clin Transl Neurol, 2018 Apr;5:445-455; Lee YC et al. J. Neurol., 2010 Oct;257:1661-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

MPZ-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2022

The MPZ c.293G>A variant is predicted to result in the amino acid substitution p.Arg98His. This variant has been reported in many individuals and families with Charcot-Marie-Tooth disease, type 1B (Ohnishi et al. 1999. PubMed ID: 10581375; Lee et al. 2010. PubMed ID: 20461396; Hsu et al. 2019. PubMed ID: 31211173; Volodarsky et al. 2020. PubMed ID: 32376792; Hayasaka et al. 1993. PubMed ID: 7688964; Gabreëls-Festen et al. 1996. PubMed ID: 8797476). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the MPZ protein (p.Arg98His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1 (PMID: 7688964, 8644725, 10581375, 12477701, 20215982). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14176). 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%. Experimental studies have shown that this missense change affects MPZ function (PMID: 20461396). For these reasons, this variant has been classified as Pathogenic. -

Sensory neuropathy;C0427065:Distal muscle weakness;C0728829:Pes cavus;C1836451:Distal lower limb amyotrophy;C1857640:Decreased nerve conduction velocity Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 19, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.0018	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.95		Loss of ubiquitination at K96 (P = 0.0506);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		1.0

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: rs121913589; hg19: chr1-161276653; COSMIC: COSV100337829; COSMIC: COSV100337829;