1-161306863-C-G

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>C(p.Arg98Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 29)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• 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, 0.992
• PP5: Variant 1-161306863-C-G is Pathogenic according to our data. Variant chr1-161306863-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306863-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.293G>C	p.Arg98Pro	missense_variant	3/6	ENST00000533357.5
MPZ	NM_001315491.2	c.293G>C	p.Arg98Pro	missense_variant	3/6
MPZ	XM_017001321.3	c.323G>C	p.Arg108Pro	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.293G>C	p.Arg98Pro	missense_variant	3/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2020	The MPZ c.293G>C; p.Arg98Pro variant (rs121913589) is reported in the literature in a family affected with Charcot-Marie-Tooth syndrome, where it co-segregated with disease in six affected individuals (Rouger 1996). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 14174). The arginine at codon 98 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (His, Cys, and Ser) have been reported in individuals with Charcot-Marie-Tooth syndrome or Dejerine-Sottas disease and are considered pathogenic (Rouger 1996, Warner 1996). Based on available information, this variant is considered to be pathogenic. References: Rouger H et al. High frequency of mutations in codon 98 of the peripheral myelin protein P0 gene in 20 French CMT1 patients. Am J Hum Genet. 1996 Mar;58(3):638-41. Warner LE et al. Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron. 1996 Sep;17(3):451-60. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The p.R98P variant (also known as c.293G>C), located in coding exon 3 of the MPZ gene, results from a G to C substitution at nucleotide position 293. The arginine at codon 98 is replaced by proline, an amino acid with dissimilar properties. This alteration was reported to segregate with disease in a family with autosomal dominant MPZ-related neuropathic disorders (Rouger H et al. Am J Hum Genet, 1996 Mar;58:638-41). Another alteration at the same codon, p.R98H (c.293G>A), has been described in multiple individuals with demyelinating Charcot-Marie-Tooth disease (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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1996

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg98 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8644725, 10581375, 20215982, 20461396). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 14174). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1 (PMID: 8644725). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 98 of the MPZ protein (p.Arg98Pro). -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of catalytic residue at R98 (P = 0.0571);
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
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;