1-161306737-G-C

Variant names:

• chr1-161306737-G-C
• rs863224449
• NM_000530.8:c.419C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000530.8(MPZ):​c.419C>G​(p.Ser140Cys) 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. S140T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.92

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 12 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr1-161306738-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-161306737-G-C is Pathogenic according to our data. Variant chr1-161306737-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215993.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8	c.419C>G	p.Ser140Cys	missense_variant	Exon 3 of 6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.419C>G	p.Ser140Cys	missense_variant	Exon 3 of 6		NP_001302420.1
MPZ	XM_017001321.3	c.449C>G	p.Ser150Cys	missense_variant	Exon 3 of 6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.419C>G	p.Ser140Cys	missense_variant	Exon 3 of 6	1	NM_000530.8	ENSP00000432943.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 30, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is region of the MPZ protein is highly conserved among many mammalian species. Codon 140 is located in the extracellular domain and this functional region mediates the adhesive properties of the protein and is critical to myelin function (PMID: 12207932). A similar missense change (p.Ser140Thr) was reported in 4 members of a family affected with Charcot-Marie-Tooth disease (PMID: 12207932). For these reasons, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant was reported in an individual affected with Charcot-Marie-Tooth type 1B (CMT1B).  This variant was also reported in this individual's son who presented with subclinical symptoms of CMT1B (PMID: 24028194). This variant has been reported in the literature and is not present in population databases. This sequence change replaces serine with cysteine at codon 140 of the MPZ protein (p.Ser140Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.018	D
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.76		Loss of disorder (P = 0.0354);
MVP		0.97
MPC		1.4
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
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: rs863224449; hg19: chr1-161276527;