NM_000530.8:c.188C>G

Variant names:

• chr1-161307304-G-C
• rs121913585
• NM_000530.8:c.188C>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PM5 PP2 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 (★★). ClinVar reports functional evidence for this variant: "SCV000329683: Published functional studies show that mice carrying the S63C variant develop neuropathy (Wrabetz et al., 2006)" and additional evidence is available in ClinVar. 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
• Publications: 20 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329683: Published functional studies show that mice carrying the S63C variant develop neuropathy (Wrabetz et al., 2006); SCV000614101: Assessment of experimental evidence suggests this variant results in abnormal protein function. PMID: 11935267, 16495463.; SCV000943102: 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).
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 14177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 neuropathy, congenital hypomyelinating, 2, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease type 2I, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain.
• 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 VariationId is 14169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZ	NM_000530.8	MANE Select	c.188C>G	p.Ser63Cys	missense	Exon 2 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.188C>G	p.Ser63Cys	missense	Exon 2 of 6	NP_001302420.1	A0A5F9ZI26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZ	ENST00000533357.5	TSL:1 MANE Select	c.188C>G	p.Ser63Cys	missense	Exon 2 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.188C>G		non_coding_transcript_exon	Exon 2 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672287.2		c.-401C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000499818.2	E9PL80

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Charcot-Marie-Tooth disease, type I (1)
-	1	-	Dejerine-Sottas disease (1)
1	-	-	DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.8
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
PromoterAI		-0.023	Neutral
Varity_R		0.91
gMVP		0.96
Mutation Taster		=0/100	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: rs121913585; hg19: chr1-161277094;