1-161306414-C-G

Position:

• chr1-161306414-C-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000533357.5(MPZ):​c.499G>C​(p.Gly167Arg) 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 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. G167A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MPZ ENST00000533357.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 1.68

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 20 ACMG points.

• PS1: Transcript ENST00000533357.5 (MPZ) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 208149
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000533357.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 1-161306414-C-G is Pathogenic according to our data. Variant chr1-161306414-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 14170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306414-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.499G>C	p.Gly167Arg	missense_variant	4/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.499G>C	p.Gly167Arg	missense_variant	4/6		NP_001302420.1
MPZ	XM_017001321.3	c.529G>C	p.Gly177Arg	missense_variant	4/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.499G>C	p.Gly167Arg	missense_variant	4/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dejerine-Sottas disease Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 18, 2012	- -

Dejerine-Sottas disease;C0205713:Roussy-Lévy syndrome;C0270912:Charcot-Marie-Tooth disease type 1B;C1843075:Charcot-Marie-Tooth disease dominant intermediate D;C1843153:Charcot-Marie-Tooth disease type 2J;C3888087:Charcot-Marie-Tooth disease type 2I;C4721436:Charcot-Marie-Tooth disease type 4E Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Mar 11, 2014

- -

DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MPZ protein function (PMID: 29687021). This missense change has been observed in individual(s) with Dejerine-Sottas disease (PMID: 7506095, 10399750, 12242557). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14170). This variant is also known as p.Gly138Arg in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 167 of the MPZ protein (p.Gly167Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.61		Gain of MoRF binding (P = 0.0404);
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.98

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: rs121913586; hg19: chr1-161276204;