rs104894619

Positions:

chr17-15231047-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP3BP4_StrongBS2

The NM_000304.4(PMP22):c.353C>T(p.Thr118Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,614,092 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 28 hom. )

Consequence

PMP22
NM_000304.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:15B:4O:2

Conservation

PhyloP100: 9.84

Variant links:

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PMP22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a chain Peripheral myelin protein 22 (size 159) in uniprot entity PMP22_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000304.4

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.04382956).

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4 linkuse as main transcript	c.353C>T	p.Thr118Met	missense_variant	5/5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9 linkuse as main transcript	c.353C>T	p.Thr118Met	missense_variant	5/5	1	NM_000304.4	ENSP00000308937	P1

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00613

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00402

AC:

1009

AN:

250976

Hom.:

AF XY:

0.00404

AC XY:

549

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00585

Gnomad NFE exome

AF:

0.00649

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00525

AC:

7669

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

3674

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00683

Gnomad4 NFE exome

AF:

0.00604

Gnomad4 OTH exome

AF:

0.00472

GnomAD4 genome

AF:

0.00364

AC:

554

AN:

152352

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

242

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00555

Gnomad4 NFE

AF:

0.00613

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00503

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00465

AC:

565

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00491

EpiControl

AF:

0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:15Benign:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:8Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants associated with autosomal dominant Charcot-Marie-Tooth disease (CMT) (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant does not segregate with disease in a manner consistent with dominant inheritance. Some literature suggests it may instead be a recessive and/or partial loss of function variant (PMID: 8252046, 16437560, 26012543, 30675404), thereby reducing severity of symptoms in patients with PMP22 duplications, while increasing severity in patients with PMP22 deletions. This variant has been reported to have a mild or lack of clinical effect in several heterozygous individuals (PMID: 8252046, 9452099, 10586280, 11081809), and also reported in one homozygous patient with a severe axonal neuropathy (PMID: 16437560). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicated this variant results in a reduction of protein transportation to the plasma membrane, with the majority sequestered in the endoplasmic reticulum. However, the effect seen in this assay was less severe than for known pathogenic variants (PMID: 10078969, 15537650, 26102530). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2024	Reported in an individual with CMT who had a pathogenic deletion of PMP22 on the opposite allele; the authors concluded p.(T118M) was likely an autosomal recessive allele because it was also identified in the individual's unaffected son (PMID: 8252046); It has been suggested that the p.(T118M) variant may modify disease severity in individuals with another PMP22 pathogenic variant (PMID: 26012543); 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: 23891399, 11081809, 26392352, 31471994, 31127728, 31357912, 20301566, 19067730, 21228398, 10078969, 7649472, 14502374, 28374912, 30675404, 30685714, 29655802, 27609586, 26102530, 31664448, 32513719, 32376792, 34426522, 26012543, 36581210, 19691535, 16437560, 10586280, 21194947, 8252046, 37703609, 36539320, 32719652) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The PMP22 c.353C>T; p.Thr118Met variant (rs104894619) is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with liability to pressure palsies (HNPP), although its clinical significance is controversial (Ho 2018, Keckarevic-Markovic 2009, Marques 2003, Nelis 1997, Roa 1993, Russo 2011, Seeman 1999, Shy 2006, Volodarsky 2021). Several reports of p.Thr118Met in affected families indicate possible recessive inheritance, as a more severe phenotype is observed in individuals carrying p.Thr118Met in trans to PMP22 deletions (Roa 1993), and at least one affected homozygote has been reported (Shy 2006). However, its inheritance pattern remains unclear, as both affected and unaffected heterozygous individuals have been also described (Ho 2018, Keckarevic-Markovic 2009, Nelis 1997, Roa 1993, Russo 2011). Further, in several families with both the p.Thr118Met variant and a pathogenic PMP22 duplication, the missense variant failed to segregate with disease (Marques 2003, Nelis 1997, Seeman 1999). The p.Thr118Met variant is found in the non-Finnish European population with an overall allele frequency of 0.66% (855/128884 alleles, including 3 homozygotes) in the Genome Aggregation Database (v2.1.1), which exceeds the estimated prevalence of CMT disease in the population (Theodom 2019). Computational analyses predict that this variant is deleterious (REVEL: 0.955). Consistent with predictions, functional studies indicate the variant protein fails to properly traffic to the plasma membrane (Schlebach 2015, Stefanski 2023). Due to conflicting information, and because a low penetrance effect cannot be ruled out, the clinical significance of the p.Thr118Met variant is uncertain at this time. References: Ho et al. T118M Variant of PMP22 Gene Presents with Painful Peripheral Neuropathy and Varying Charcot-Marie-Tooth Features: A Case Series and Review of the Literature. Case Rep Genet. 2018 Dec 25;2018:2618071. PMID: 30675404. Keckarevic-Markovic et al. Mutational analysis of GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in Serbian Charcot-Marie-Tooth patients. J Peripher Nerv Syst. 2009; 14(2): 125-136. PMID: 19691535. Marques et al. Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication. Braz J Med Biol Res. 2003; 36(10): 1403-1407. PMID: 14502374. Nelis et al. PMP22 Thr(118)Met: recessive CMT1 mutation or polymorphism? Nat Genet. 1997; 15(1): 13-14. PMID: 8988161. Roa et al. Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. Nat Genet. 1993; 5(2): 189-194. PMID: 8252046. Russo et al. Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul Disord. 2011; 21(2): 106-114. PMID: 21194947. Schlebach et al. Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22. J Am Chem Soc. 2015; 137(27): 8758-8768. PMID: 26102530. Seeman et al. Charcot-Marie-Tooth 1A: heterozygous T118M mutation over a CMT1A duplication has no influence on the phenotype. Ann N Y Acad Sci. 1999; 883: 485-489. PMID: 10586280. Shy et al. T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. Ann Neurol. 2006; 59(2): 358-364. PMID: 16437560. Stefanski KM et al. How T118M peripheral myelin protein 22 predisposes humans to Charcot-Marie-Tooth disease. J Biol Chem. 2023 Feb;299(2):102839. PMID: 36581210. Theadom et al. Prevalence of Charcot-Marie-Tooth disease across the lifespan: a population-based epidemiological study. BMJ Open. 2019 Jun 14;9(6):e029240. PMID: 31203252. Volodarsky et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PMP22: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Hereditary liability to pressure palsies

Pathogenic:1Uncertain:2Benign:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jul 04, 2018	This variant was also detected in the proband's father, who was found to have myopathic changes on EMG. This does not fully explain the proband's features but may be contributing to her phenotype. -

Charcot-Marie-Tooth disease

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Inherited Neuropathy Consortium	-	- -

Charcot-Marie-Tooth disease, type I

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 118 of the PMP22 protein (p.Thr118Met). This variant is present in population databases (rs104894619, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in individuals and families with Charcot-Marie-Tooth disease type 1A (PMID: 16437560, 8988161, 8252046, 19691535, 21194947, 26392352). It has been reported as a dominantly inherited variant with reduced penetrance because both heterozygous affected (PMID: 21194947) and heterozygous unaffected individuals have been observed in several families (PMID: 8252046, 10586280). It has also been reported as a recessively inherited, partial loss of function allele based on observations of individuals with a more severe phenotype who presented as compound heterozygous for this allele along with a PMP22 deletion allele (PMID: 8252046, 26012543), and one individual with a more severe phenotype who was homozygous for this allele (PMID: 16437560). ClinVar contains an entry for this variant (Variation ID: 8431). 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. Functional studies show this variant is retained in the cytoplasm, albeit to a lesser extent compared to other PMP22 variants (PMID: 10078969). In addition, it leads to altered nuclei with an apoptotic-like phenotype when expressed in COS cells but not when co-expressed with wild type PMP22, which could be consistent with a recessive mode of inheritance in contrast to other PMP22 variants (PMID: 7649472). In summary, this variant has been reported to be dominantly inherited in individuals with CMT1A and it has also been reported to be recessively inherited in individuals with CMT1A who have presented with a more severe phenotype. This variant has also been shown to mildly disrupt protein function. However, the pathogenicity of this variant is much debated because it is present at a high frequency in the general population and it has been observed in unaffected and affected individuals within the same family. For these reasons, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Charcot-Marie-Tooth disease, type IA

Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 29, 2018	- -

Charcot-Marie-Tooth disease, type 1a, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Tip-toe gait

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Mar 05, 2021

The heterozygous variant c.353C> T p. (Thr118Met) was detected in the PMP22 gene [dbSNP rs104894619; frequency T = 0.468% (ExAC)]. In the literature [Shy (2006) Ann Neurol 59: 358; Keckarevic-Markovic (2009) J Peripher Nerv Syst 14: 125; Russo (2011) Neuromuscul Disord 21: 106 and Ho (2018) Case Rep Genet 2018: 2618071] this variant is associated with hereditary neuropathies. However, the authors refer to numerous older studies in which it is controversially discussed and in some cases it is assigned an unclear clinical effect up to and including classification as a non-pathological polymorphism. These very inconsistent and controversial classifications are reflected in the databases ClinVar [4x pathogenic, 13x VUS, 3x likely / benign] and LOVD [7x pathogenic, 5x VUS, 2x likely benign]. A "reduced penetrance" [Russo (2011) Neuromuscul Disord 21: 106] of the proven variant is being discussed, since it was also demonstrated in control groups of the studies. In addition, a partial loss of function was observed for the protein affected by the variant depending on the genotype [Shy (2006) Ann Neurol 59: 358]. Modulating effects due to variants in other genes cannot be ruled out either. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 31, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;.;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.044

T;T;T;T

MetaSVM

Pathogenic

0.79

MutationAssessor

Pathogenic

3.3

M;M;M;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.5

.;D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;.

Polyphen

1.0

D;D;D;.

Vest4

0.85

MVP

0.95

MPC

1.3

ClinPred

0.045

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.79

gMVP

0.89

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over