Submissions for variant NM_000304.4(PMP22):c.353C>T (p.Thr118Met)

gnomAD frequency: 0.00378  dbSNP: rs104894619

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194789	SCV000248536	uncertain significance	not specified	2015-07-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197572	SCV000254521	uncertain significance	Charcot-Marie-Tooth disease, type I	2024-01-28	criteria provided, single submitter	clinical testing	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224441	SCV000280814	uncertain significance	not provided	2016-01-18	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000224441	SCV000292667	uncertain significance	not provided	2024-04-07	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000224441	SCV000331367	uncertain significance	not provided	2015-08-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000197572	SCV000400717	likely benign	Charcot-Marie-Tooth disease, type I	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000008946	SCV000400718	likely benign	Hereditary liability to pressure palsies	2016-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224441	SCV000493173	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PMP22: BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224441	SCV000604882	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	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.
Undiagnosed Diseases Network, NIH	RCV000008946	SCV000837683	uncertain significance	Hereditary liability to pressure palsies	2018-07-04	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000224441	SCV000843297	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	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).
Mendelics	RCV000008946	SCV001140306	benign	Hereditary liability to pressure palsies	2023-08-22	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001027473	SCV001337038	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000032119	SCV001429193	uncertain significance	Charcot-Marie-Tooth disease, type IA	2018-10-29	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001507314	SCV001712107	likely pathogenic	Tip-toe gait	2021-03-05	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224441	SCV001712896	uncertain significance	not provided	2022-02-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000224441	SCV003811204	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000224441	SCV005197197	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000008945	SCV000029155	pathogenic	Charcot-Marie-Tooth disease, type 1a, autosomal recessive	2009-03-01	no assertion criteria provided	literature only
OMIM	RCV000008946	SCV000053463	pathogenic	Hereditary liability to pressure palsies	2009-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000032119	SCV000055665	not provided	Charcot-Marie-Tooth disease, type IA		no assertion provided	literature only
GeneReviews	RCV000008946	SCV000086759	not provided	Hereditary liability to pressure palsies		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000008946	SCV000929043	uncertain significance	Hereditary liability to pressure palsies		no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV001027473	SCV001190043	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	provider interpretation