rs121913605

Positions:

• chr1-161307306-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The NM_000530.8(MPZ):​c.186C>G​(p.Ile62Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I62F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 1.63

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000530.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161307308-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 14189.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.186C>G	p.Ile62Met	missense_variant	2/6	ENST00000533357.5
MPZ	NM_001315491.2	c.186C>G	p.Ile62Met	missense_variant	2/6
MPZ	XM_017001321.3	c.216C>G	p.Ile72Met	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.186C>G	p.Ile62Met	missense_variant	2/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251308 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2I Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 14, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 25, 2003	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2023	The MPZ c.186C>G; p.Ile62Met variant is reported in the literature in one individual affected with late onset Charcot-Marie-Tooth 2 syndrome (Auer-Grumbach 2003). This variant is also reported in ClinVar (Variation ID: 14194) and is found in the non-Finnish European population with an overall allele frequency of 0.0012% (3/251308 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.184A>T, p.Ile62Phe) has been reported in four related individuals with autosomal dominant motor and sensory neuropathy with focally folded myelin sheaths (Nakagawa 1999) and in vitro functional analysis of the p.Ile62Phe variant demonstrated dysregulation of adhesion function of the MPZ protein associated with abnormal myelin folding (Matsuyama 2002). Computational analyses of the p.Ile62Met, however, are uncertain whether this variant is neutral or deleterious (REVEL: 0.276). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Auer-Grumbach M et al. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology. 2003 Nov 25;61(10):1435-7. PMID: 14638973. Nakagawa M et al. A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths. Neurology. 1999 Apr 12;52(6):1271-5. PMID: 10214757. Matsuyama W et al. Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B. Acta Neuropathol. 2002 May;103(5):501-8. PMID: 11935267. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2024	Has been reported previously in individuals with features of Charcot-Marie-Tooth (CMT) (PMID: 14638973, 19259128, 37747677); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26135405, 19259128, 15249646, 26310628, 20461396, 36567457, 37091313, 14638973, 37747677) -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Nov 15, 2022

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Roussy-Lévy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 27, 2019

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP5. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ile62 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10214757, 11935267). 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 not expected to disrupt MPZ protein function. ClinVar contains an entry for this variant (Variation ID: 14194). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14638973). This variant is present in population databases (rs121913605, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 62 of the MPZ protein (p.Ile62Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	0.97	A;A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.28
Sift	Benign	0.071	T
Sift4G	Benign	0.093	T
Polyphen		0.53	P
Vest4		0.82
MutPred		0.48		Gain of catalytic residue at V58 (P = 0.0487);
MVP		0.93
MPC		1.1
ClinPred		0.37	T
GERP RS		4.4
Varity_R		0.35
gMVP		0.93

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: rs121913605; hg19: chr1-161277096;