rs879253858

chr1-161306753-T-Achr1-161306753-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM1 PM2 PM5 PP5_Very_Strong

The NM_000530.8(MPZ):c.403A>T(p.Ile135Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I135M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.94

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.

• PS1: Transcript NM_000530.8 (MPZ) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 243089
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr1-161306752-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-161306753-T-A is Pathogenic according to our data. Variant chr1-161306753-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 861910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306753-T-A is described in UniProt as null. Variant chr1-161306753-T-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.403A>T	p.Ile135Leu	missense_variant	3/6	ENST00000533357.5
MPZ	NM_001315491.2	c.403A>T	p.Ile135Leu	missense_variant	3/6
MPZ	XM_017001321.3	c.433A>T	p.Ile145Leu	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.403A>T	p.Ile135Leu	missense_variant	3/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is not observed in the gnomAD v2.1.1 dataset. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000861910). A different missense change at the same codon (p.Ile135Thr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014172). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile135 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8664899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Dejerine-Sottas syndrome (PMID: 12090401). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 135 of the MPZ protein (p.Ile135Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.35
Sift	Benign	0.066	T
Sift4G	Benign	0.14	T
Polyphen		0.026	B
Vest4		0.68
MutPred		0.61		Loss of methylation at K138 (P = 0.065);
MVP		0.89
MPC		0.55
ClinPred		0.94	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879253858; hg19: chr1-161276543;