chr1-161306843-G-A

Variant names:

• chr1-161306843-G-A
• NM_000530.8:c.313C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000530.8(MPZ):​c.313C>T​(p.Pro105Ser) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P105T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.50

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr1-161306842-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8	c.313C>T	p.Pro105Ser	missense_variant	Exon 3 of 6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.313C>T	p.Pro105Ser	missense_variant	Exon 3 of 6		NP_001302420.1
MPZ	XM_017001321.3	c.343C>T	p.Pro115Ser	missense_variant	Exon 3 of 6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.313C>T	p.Pro105Ser	missense_variant	Exon 3 of 6	1	NM_000530.8	ENSP00000432943.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Apr 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MPZ c.313C>T; p.Pro105Ser variant (rs121913609, ClinVar variation ID: 1485347) is reported in the literature in one individual affected with Charcot-Marie-Tooth disease (Fridman 2023). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.314C>T, p.Pro105Leu; c.313C>A; p.Pro105Thr) have been reported in individuals with Charcot-Marie-Tooth disease (Kabzinska 2007, Lorance 2018). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.349). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Fridman V et al. Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study. Ann Neurol. 2023 Mar;93(3):563-576. PMID: 36203352. Kabzinska D et al. Late-onset Charcot-Marie-Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene. Am J Med Genet A. 2007 Sep 15;143A(18):2196-9. PMID: 17663472. Lorance DK et al. Novel Myelin Protein Zero Mutation in 3 Generations of Vermonters With Demyelinating Charcot-Marie-Tooth Disease. J Clin Neuromuscul Dis. 2018 Mar;19(3):101-107. PMID: 29465609. -

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

Feb 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Pro105 ‚Äãamino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29465609, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing This sequence change replaces proline with serine at codon 105 of the MPZ protein (p.Pro105Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MPZ-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.57		Gain of catalytic residue at P105 (P = 0.057);
MVP		0.68
MPC		1.5
ClinPred		0.95	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-161276633;