rs267607247

Variant names:

• chr1-161305953-C-A
• rs267607247
• NM_000530.8:c.670G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000530.8(MPZ):​c.670G>T​(p.Asp224Tyr) 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 5.69

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 1-161305953-C-A is Pathogenic according to our data. Variant chr1-161305953-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161305953-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8	c.670G>T	p.Asp224Tyr	missense_variant	Exon 6 of 6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.670G>T	p.Asp224Tyr	missense_variant	Exon 6 of 6		NP_001302420.1
MPZ	XM_017001321.3	c.675+155G>T		intron_variant	Intron 5 of 5		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.670G>T	p.Asp224Tyr	missense_variant	Exon 6 of 6	1	NM_000530.8	ENSP00000432943.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Inborn genetic diseases Pathogenic:1

Apr 23, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D224Y variant (also known as c.670G>T), located in coding exon 6 of the MPZ gene, results from a G to T substitution at nucleotide position 670. The aspartic acid at codon 224 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was detected as heterozygous in multiple unrelated individuals with a consistent disease phenotype that includes sensory deficits, pes cavus, diminished nerve conduction velocities, and absent or diminished reflexes (Fabrizi GM et al. Neuromuscul Disord, 2006 Mar;16:183-7; Miltenberger-Miltenyi G et al. Eur J Hum Genet, 2009 Sep;17:1154-9; Benedetti S et al. Arch Neurol, 2010 Dec;67:1498-505; Schneider-Gold C et al. Muscle Nerve, 2010 Apr;41:550-4). In the heterozygous state, this alteration segregated with disease in one family (Schneider-Gold C et al. Muscle Nerve, 2010 Apr;41:550-4). This variant was also detected as homozygous in two affected individuals in the same family (Fabrizi GM et al. Neuromuscul Disord, 2006 Mar;16:183-7). Biochemical and structural analyses suggest that this alteration leads to structural changes that can contribute to hypermyelination (Raasakka A et al. PLoS One, 2019 Jun;14:e0216833). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Nov 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 224 of the MPZ protein (p.Asp224Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 16488608, 19259128, 19882637, 21149811, 27088055). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41024). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPZ function (PMID: 31173589). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

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Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.81	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;T
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.74		Gain of sheet (P = 0.0344);.;
MVP		0.95
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267607247; hg19: chr1-161275743;