ClinVar Miner

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

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000194789 SCV000604882 uncertain significance not specified 2017-01-16 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000224441 SCV000843297 uncertain significance not provided 2018-04-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224441 SCV000493173 likely pathogenic not provided 2016-08-31 criteria provided, single submitter clinical testing
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224441 SCV000331367 uncertain significance not provided 2015-08-24 criteria provided, single submitter clinical testing
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.
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.
Genetic Services Laboratory, University of Chicago RCV000194789 SCV000248536 uncertain significance not specified 2015-07-31 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
Inherited Neuropathy Consortium RCV000008946 SCV000929043 uncertain significance Hereditary liability to pressure palsies no assertion criteria provided literature only
Invitae RCV000197572 SCV000254521 uncertain significance Charcot-Marie-Tooth disease, type I 2018-12-24 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.
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
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.

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