chr1-161307308-T-A

Variant names:

• chr1-161307308-T-A
• rs121913602
• NM_000530.8:c.184A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_000530.8(MPZ):​c.184A>T​(p.Ile62Phe) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I62M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.381
• Publications: 7 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 7 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 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.
• PP5: Variant 1-161307308-T-A is Pathogenic according to our data. Variant chr1-161307308-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14189.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000530.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZ	NM_000530.8	MANE Select	c.184A>T	p.Ile62Phe	missense	Exon 2 of 6	NP_000521.2
	MPZ	NM_001315491.2		c.184A>T	p.Ile62Phe	missense	Exon 2 of 6	NP_001302420.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZ	ENST00000533357.5	TSL:1 MANE Select	c.184A>T	p.Ile62Phe	missense	Exon 2 of 6	ENSP00000432943.1
	MPZ	ENST00000463290.5	TSL:1	n.184A>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000431538.1
	MPZ	ENST00000672602.2		c.184A>T	p.Ile62Phe	missense	Exon 2 of 6	ENSP00000500814.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced protein expression and functionality (PMID: 11935267); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8310815, 26310628, 20461396, 11935267, 33179255, 10214757)

CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B, WITH FOCALLY FOLDED MYELIN SHEATHS Pathogenic:1

Apr 12, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.38
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.037	D
Sift4G	Uncertain	0.057	T
Polyphen		0.97	D
Vest4		0.84
MutPred		0.47		Loss of stability (P = 0.1775)
MVP		0.98
MPC		1.4
ClinPred		0.69	D
GERP RS		-0.051
PromoterAI		0.031	Neutral
Varity_R		0.55
gMVP		0.98
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913602; hg19: chr1-161277098;