ClinVar Miner

Submissions for variant NM_024577.4(SH3TC2):c.2860C>T (p.Arg954Ter) (rs80338933)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168436 SCV000219133 pathogenic Charcot-Marie-Tooth disease type 4 2019-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg954*) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80338933, ExAC 0.1%). This variant is clearly defined as a Charcot-Marie-Tooth causative allele (PMID: 14574644, 16924012, 18511281, 19272779). It has been reported in several European populations and is a founder mutation in the French-Canadian population (PMID: 18511281). ClinVar contains an entry for this variant (Variation ID: 2482). Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). For these reasons, this variant has been classified as Pathogenic.
UCLA Clinical Genomics Center, UCLA RCV000002586 SCV000255465 pathogenic Charcot-Marie-Tooth disease, type 4C 2014-04-15 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255213 SCV000255843 pathogenic not provided 2019-03-22 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
GeneDx RCV000255213 SCV000321943 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing The R954X variant has been reported many times in association with CMT4C (Senderek et al., 2003; Azzedine et al., 2006; Gosselin et al., 2008; Houlden et al., 2009; Lupski et al., 2010; Hoyer et al., 2014; Varley et al., 2015). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, R954X has been identified in the homozygous state in several unrelated patients referred for testing at GeneDx. Therefore, R954X is interpreted to be a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255213 SCV000339051 pathogenic not provided 2017-04-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000282937 SCV000454536 pathogenic SH3TC2-Related Disorders 2018-03-20 criteria provided, single submitter clinical testing The SH3TC2 c.2860C>T (p.Arg954Ter) variant is a stop-gained variant and is predicted to result in premature termination of the protein. The p.Arg954Ter variant is reported in at least nine studies associated with Charcot-Marie-Tooth, type 4, and found in a total of 39 unrelated patients including 26 homozygotes and 13 compound heterozygote (Senderek et al. 2003; Azzedine et al. 2006; Lupo et al. 2009; Gosselin et al. 2008; Houlden et al. 2009; Lupski et al. 2010; Baets et al. 2011; Hoyer et al. 2014; Varley et al. 2015). The p.Arg954Ter variant is reported once in association with mononeuropathy of the median nerve. Lupski et al. (2010) report a family affected with autosomal recessive Charcot-Marie-Tooth, type 4 which includes three family members who are heterozygous for the p.Arg954Ter variant and present with a subtle mild mononeuropathy of the median nerve. The p.Arg954Ter variant has been shown to segregate with disease in a recessive inheritance pattern in at least two families (Lupski et al. 2010; Varley et al. 2015). The variant was reported in five of 180 controls in a heterozygous state, consistent with carrier status, and at a frequency of 0.00141 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and potential impact of stop-gained variants, the p.Arg954Ter variant is classified as pathogenic for SH3TC2-related disorders. It is most frequently described in association with autosomal recessive Charcot-Marie-Tooth, type 4, but has also been described in association with a mild presentation of dominantly inherited mononeuropathy of the median nerve. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics,Fulgent Genetics RCV000515338 SCV000611317 pathogenic Charcot-Marie-Tooth disease, type 4C; Mononeuropathy of the median nerve, mild 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622836 SCV000741997 pathogenic Inborn genetic diseases 2017-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000002586 SCV000882617 likely pathogenic Charcot-Marie-Tooth disease, type 4C 2018-10-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000484 SCV001157366 pathogenic not specified 2018-10-01 criteria provided, single submitter clinical testing The SH3TC2 c.2860C>T; p.Arg954Ter variant (rs80338933) has been reported in the homozygous and compound heterozygous states in multiple families and individuals diagnosed with Charcot-Marie-Tooth disease type 4C (CMT4C) and was determined to be the most prevalent pathogenic variant in a cohort of CMT4C patients from the Czech Republic (Baets 2011, Hoyer 2014, Lassuthova 2011, Lupski 2010, Senderek 2003, Varley 2015). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.12% in the non-Finnish European population (identified in 158 out of 126,576 chromosomes), and is classified as pathogenic in ClinVar (Variant ID: 2482). The p.Arg954Ter variant introduces a premature stop codon in exon 11 and is expected to result in a truncated or absent protein product. Therefore, based on the available evidence, the p.Arg954Ter variant is classified as pathogenic. Baets et al. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011 Sep;134(Pt 9):2664-76. doi: 10.1093/brain/awr184. Epub 2011 Aug 11. Hoyer et al. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int. 2014;2014:210401. doi: 10.1155/2014/210401. Epub 2014 Jun 16. Lassuthova et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet. 2011 Oct;80(4):334-45. doi: 10.1111/j.1399-0004.2011.01640.x. Epub 2011 Mar 1. Lupski et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010 Apr 1;362(13):1181-91. doi: 10.1056/NEJMoa0908094. Epub 2010 Mar 10. Senderek et al. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet. 2003 Nov;73(5):1106-19. Epub 2003 Oct 21. Varley et al. Phenotypic variability of CMT4C in a French-Canadian kindred. Muscle Nerve. 2015 Sep;52(3):444-9. doi: 10.1002/mus.24640. Epub 2015 May 14.
Institute of Human Genetics,Klinikum rechts der Isar RCV000002586 SCV001162825 pathogenic Charcot-Marie-Tooth disease, type 4C 2020-01-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255213 SCV001249577 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000144877 SCV001335894 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255213 SCV001433786 pathogenic not provided 2017-11-09 criteria provided, single submitter clinical testing The p.Arg954Ter variant (rs80338933) has been reported in the homozygous and compound heterozygous states in multiple families and individuals diagnosed with Charcot-Marie-Tooth disease type 4C (CMT4C) and was determined to be the most prevalent pathogenic variant in a cohort of CMT4C patients from the Czech Republic (Baets 2011, Høyer 2014, Laššuthová 2011, Lupski 2010, Senderek 2003, Varley 2015). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.12% in the non-Finnish European population (identified in 158 out of 126,576 chromosomes), and is classified as pathogenic in ClinVar (Variant ID: 2482). The p.Arg954Ter variant introduces a premature stop codon in exon 11 and is expected to result in a truncated or absent protein product. Therefore, based on the available evidence, the p.Arg954Ter variant is classified as pathogenic.
OMIM RCV000002586 SCV000022744 pathogenic Charcot-Marie-Tooth disease, type 4C 2010-04-01 no assertion criteria provided literature only
OMIM RCV000002587 SCV000022745 pathogenic Mononeuropathy of the median nerve, mild 2010-04-01 no assertion criteria provided literature only
GeneReviews RCV000002586 SCV000041492 pathologic Charcot-Marie-Tooth disease, type 4C 2008-03-31 no assertion criteria provided curation Converted during submission to Pathogenic.
Dept. of Medical Genetics, Telemark Hospital Trust RCV000144877 SCV000172149 pathogenic Charcot-Marie-Tooth disease 2013-11-01 no assertion criteria provided research Observed in four sporadic individuals

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.