1-161307304-G-C

Position:

• chr1-161307304-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000530.8(MPZ):​c.188C>G​(p.Ser63Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 5.82

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 9 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 chr1-161307304-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 1-161307304-G-C is Pathogenic according to our data. Variant chr1-161307304-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161307304-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.188C>G	p.Ser63Cys	missense_variant	2/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.188C>G	p.Ser63Cys	missense_variant	2/6		NP_001302420.1
MPZ	XM_017001321.3	c.218C>G	p.Ser73Cys	missense_variant	2/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.188C>G	p.Ser63Cys	missense_variant	2/6	1	NM_000530.8	ENSP00000432943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	Published functional studies show that mice carrying the S63C variant develop neuropathy (Wrabetz et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 7506095, 16495463, 26310628, 20461396, 27535533, 11935267, 6099985) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 24, 2022	This variant has been identified in at least one individual with Dejerine-Sottas disease and appears to occur de novo in one individual. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 11935267, 16495463. The variant is located in a region that is considered important for protein function and/or structure. -

DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser63 amino acid residue in MPZ. Other variant that disrupt this residue have been observed in affected individuals (PMID: 22734905, 7693130, 12402337, 8835320), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies using transgenic mouse models have shown that this missense change [p.Ser63Cys] creates a packing defect in the myelin sheath that leads to hypomyelination and these mice develop tremor, ataxia, weakness and muscle atrophy of hind limbs recapitulating phenotypes observed in human neuromuscular disease (PMID: 16495463, 20937820). This variant has been observed to be de novo in an individual affected with Dejerine-Sottas syndrome (PMID: 7506095). ClinVar contains an entry for this variant (Variation ID: 14169). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 63 of the MPZ protein (p.Ser63Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. -

Dejerine-Sottas disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.68		Loss of disorder (P = 0.1481);
MVP		0.81
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.96

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: rs121913585; hg19: chr1-161277094;