ClinVar Miner

Submissions for variant NM_000304.4(PMP22):c.353C>T (p.Thr118Met) (rs104894619)

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Total submissions: 20
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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
Invitae RCV000197572 SCV000254521 uncertain significance Charcot-Marie-Tooth disease, type I 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 118 of the PMP22 protein (p.Thr118Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs104894619, ExAC 0.7%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). 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). 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 2018-06-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PMP22 gene. The T118M variant was previously identified in an individual with CMT1 who also had a pathogenic PMP22 duplication; the authors concluded T118M was likely a benign variant because it was also identified in unaffected relatives and it did not segregate with the CMT1 phenotype in the family (Seeman et al., 1999). This variant was also reported in an individual with CMT who had a pathogenic deletion of PMP22 on the opposite allele; the authors concluded T118M was likely an autosomal recessive allele because it was also identified in the individual's unaffected son (Roa et al., 1993). However, the T118M variant has also been identified in individuals with CMT1 who did not have another identifiable pathogenic variant (Keckarevic-Markovic et al., 2009; Russo et al., 2011), as a heterozygous variant in individuals with an HNPP-like phenotype (Russo et al., 2011), and as a homozygous variant in an individual with a severe axonal neuropathy (Shy et al., 2006). It has been suggested that the T118M variant may modify disease severity in individuals with another PMP22 pathogenic variant (Jerath et al., 2015). The T118M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the T118M variant is observed in 1152/276810 (0.4%) alleles in large population cohorts, including five individuals who are homozygous for T118M (Lek et al., 2016). Based on the currently available information, it is unclear whether the T118M variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224441 SCV000331367 uncertain significance not provided 2015-08-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000197572 SCV000400717 likely benign Charcot-Marie-Tooth disease, type I 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000008946 SCV000400718 likely benign Hereditary liability to pressure palsies 2016-06-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224441 SCV000493173 likely benign not provided 2019-12-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282781 SCV000604882 uncertain significance none provided 2019-09-25 criteria provided, single submitter clinical testing The p.Thr118Met variant (rs104894619) has been studied extensively, and its contribution to phenotypes associated with Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with liability to pressure palsies (HNPP) remains controversial. Early reports of p.Thr118Met in affected families suggested that this variant could act recessively, due to observations that a more severe phenotype was observed when p.Thr118Met was identified in trans to PMP22 deletions (creating a hemizygous p.Thr118Met allele), yet heterozygous carries were asymptomatic (Roa 1993 and Marques 2003). To date, no clearly asymptomatic individuals homozygous for the p.Thr118Met variant have been reported, and thus the notion that this variant is indeed recessive cannot be formally excluded. However, data do suggest that p.Thr118Met does not modify the phenotype associated with PMP22 duplication, as this variant has been shown to segregate independently from all symptoms in affected families (Nelis 1997 and Seeman 1999). Other reports suggest that, despite the relatively high population frequency of p.Thr118Met (0.73% in Europeans in the Exome Aggregation Consortium (ExAC) browser; identified in 530 out of 72,640 chromosomes, including 2 homozygotes), this variant could act as a low penetrance dominant allele, as it has been identified as a heterozygote in several individuals/pedigrees with symptoms of HNPP or CMT who tested negative for other common causative variants (Shy 2006, Keckarevic-Markovic 2009, Russo 2011). Additionally, the threonine codon 118 is highly conserved considering 12 species up to Zebrafish (Alamut software v2.8.1), and functional assays indicate this variant imparts measurable defects in PMP22 such as protein folding and trafficking (Schlebach 2015). Thus, due to conflicting and incomplete available information (further complicated by the genetic heterogeneity and variable penetrance and expressivity of genes and alleles associated with CMT), the clinical significance of the p.Thr118Met variant cannot be determined with certainty.
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 Inc RCV000224441 SCV000843297 uncertain significance not provided 2020-09-09 criteria provided, single submitter clinical testing
Mendelics RCV000008946 SCV001140306 uncertain significance Hereditary liability to pressure palsies 2019-05-28 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
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 pathologic Charcot-Marie-Tooth disease, type IA 2012-10-18 no assertion criteria provided curation Converted during submission to Pathogenic.
GeneReviews RCV000008946 SCV000086759 pathologic Hereditary liability to pressure palsies 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
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

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