NM_000530.8:c.382G>A

Variant names:

• chr1-161306774-C-T
• rs267607243
• NM_000530.8:c.382G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000530.8(MPZ):​c.382G>A​(p.Asp128Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. D128E) has been classified as Uncertain significance.

• 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: 3.52
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
• neuropathy, congenital hypomyelinating, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease dominant intermediate D

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 2I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 2J

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 84 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.98749 (below the threshold of 3.09). Trascript score misZ: 1.4782 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease type 1B, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, Charcot-Marie-Tooth disease type 2J, neuropathy, congenital hypomyelinating, 2, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 1-161306774-C-T is Pathogenic according to our data. Variant chr1-161306774-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242747.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161306774-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242747.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161306774-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242747.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161306774-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242747.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161306774-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242747.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.382G>A	p.Asp128Asn	missense_variant	Exon 3 of 6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.382G>A	p.Asp128Asn	missense_variant	Exon 3 of 6		NP_001302420.1
MPZ	XM_017001321.3	c.412G>A	p.Asp138Asn	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.382G>A	p.Asp128Asn	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

Nov 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 10463363). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 128 of the MPZ protein (p.Asp128Asn). ClinVar contains an entry for this variant (Variation ID: 242747). 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.Asp128 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been observed in individuals with MPZ-related conditions (PMID: 9888385, 18636082), which suggests that this may be a clinically significant amino acid residue. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). -

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	0.97
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.64		Gain of ubiquitination at K130 (P = 0.0931);
MVP		0.71
MPC		1.4
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.97
Mutation Taster		=197/103	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267607243; hg19: chr1-161276564;