rs121913601

chr1-161307259-G-Achr1-161307259-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000530.8(MPZ):c.233C>T(p.Ser78Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S78W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MPZ NM_000530.8 missense, splice_region
• Scores: Splicing: ADA: 0.9800
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.75

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 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr1-161307259-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-161307259-G-A is Pathogenic according to our data. Variant chr1-161307259-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161307259-G-A is described in Lovd as [Pathogenic]. Variant chr1-161307259-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.233C>T	p.Ser78Leu	missense_variant, splice_region_variant	2/6	ENST00000533357.5
MPZ	NM_001315491.2	c.233C>T	p.Ser78Leu	missense_variant, splice_region_variant	2/6
MPZ	XM_017001321.3	c.263C>T	p.Ser88Leu	missense_variant, splice_region_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.233C>T	p.Ser78Leu	missense_variant, splice_region_variant	2/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26310628, 26135405, 26481167, 25429913, 19691535, 19293842, 7527371, 19259128, 11545686, 10965800, 11437164, 9633821, 9187667, 11835375, 12497641, 10093067, 7550231, 18347322, 26406915, 18422810, 29687021, 32376792, 33825325, 12707985, 9883862, 20461396) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 01, 2022	This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant Charcot-Marie-Tooth disease and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. In some published literature, this variant is referred to as p.Ser49Leu. The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MPZ: PS4, PM1, PM2, PM5, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2015	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease, type 1b, with focally folded myelin sheaths Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 78 of the MPZ protein (p.Ser78Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type I (PMID: 7527371, 9633821, 10965800, 18347322). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14188). 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. This variant disrupts the p.Ser78 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7527371, 9633821, 12707985, 18347322; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.51		Loss of disorder (P = 0.045);
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
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

Publications

LitVar

Other links and lift over

dbSNP: rs121913601; hg19: chr1-161277049; COSMIC: COSV105205610; COSMIC: COSV105205610;