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

gnomAD frequency: 0.00067  dbSNP: rs80338933

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168436	SCV000219133	pathogenic	Charcot-Marie-Tooth disease type 4	2024-01-29	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. Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs80338933, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14574644, 16924012, 18511281, 19272779). It is commonly reported in individuals of French-Canadian ancestry (PMID: 18511281). ClinVar contains an entry for this variant (Variation ID: 2482). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000255213	SCV000255843	pathogenic	not provided	2021-07-07	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
GeneDx	RCV000255213	SCV000321943	pathogenic	not provided	2021-09-28	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21840889, 18511281, 28981955, 29243538, 30001926, 28726809, 29653220, 30653784, 30373780, 16924012, 25737037, 23806086, 20220177, 25525159, 25025039, 27231023, 19272779, 27549087, 27296017, 14574644, 29321516, 21291453, 31028937, 31346473, 31634715, 31827005, 31980526, 33386210, 25736553, 34426522, 34169998, 32376792, 31589614, 33643188, 32909314, 33726816)
Eurofins Ntd Llc (ga)	RCV000255213	SCV000339051	pathogenic	not provided	2017-04-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000282937	SCV000454536	pathogenic	SH3TC2-related disorder	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; Susceptibility to mononeuropathy of the median nerve, mild	2022-04-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622836	SCV000741997	pathogenic	Inborn genetic diseases	2023-06-23	criteria provided, single submitter	clinical testing	The c.2860C>T (p.R954*) alteration, located in exon 11 (coding exon 11) of the SH3TC2 gene, consists of a C to T substitution at nucleotide position 2860. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 954. Premature stop codons are typically deleterious in nature (Richards, 2015). Based on data from gnomAD, the T allele has an overall frequency of 0.073% (206/282718) total alleles studied. The highest observed frequency was 0.125% (9/7224) of Other alleles. This alteration has been reported either homozygous or compound heterozygous with another SH3TC2 variant in multiple individuals with Charcot-Marie-Tooth (CMT) disease and presenting with similar symptoms as the proband (Senderek, 2003; Lupski, 2010; Baets, 2011; Høyer, 2014; Laššuthová, 2016). This mutation is reported to cause CMT1 in several different populations (Høyer, 2014). Based on the available evidence, this alteration is classified as pathogenic.
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	RCV000255213	SCV001157366	pathogenic	not provided	2021-07-21	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, 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. 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 Munich, Klinikum Rechts Der Isar, TU München	RCV000002586	SCV001162825	pathogenic	Charcot-Marie-Tooth disease type 4C	2020-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255213	SCV001249577	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SH3TC2: PM3:Very Strong, PVS1, PM2, PP4
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000144877	SCV001335894	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002586	SCV001440841	pathogenic	Charcot-Marie-Tooth disease type 4C	2023-10-25	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM3_SUP
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255213	SCV001447202	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000002587	SCV001448826	pathogenic	Susceptibility to mononeuropathy of the median nerve, mild	2019-02-22	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255213	SCV001449826	likely pathogenic	not provided	2015-12-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255213	SCV002021249	pathogenic	not provided	2023-11-30	criteria provided, single submitter	clinical testing
DASA	RCV000002587	SCV002061216	pathogenic	Susceptibility to mononeuropathy of the median nerve, mild	2022-01-05	criteria provided, single submitter	clinical testing	The c.2860C>T;p.(Arg954*) variant creates a premature translational stop signal in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(Clinvar ID: 2482; PMID: 31346473; 30653784; 27231023; 25737037; 25326637; 25025039; 23806086) - PS4. The p.(Arg954*) was detected in trans with a pathogenic variant (PMID: 31346473; 30653784; 27231023; PMID: 25737037; 25326637; 25025039; 23806086) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25737037; 23806086) - PP1_strong and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000255213	SCV002064388	pathogenic	not provided	2018-06-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SH3TC2 gene demonstrated a sequence change, c.2860C>T, which results in the creation of a premature stop codon at amino acid position 954, p.Arg954*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SH3TC2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple patients with SH3TC2-related Charcot-Marie-Tooth disease type 4C (Senderek et al., 2003; Houlden et al., 2009.).
Mayo Clinic Laboratories, Mayo Clinic	RCV000255213	SCV002520029	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000002586	SCV002556765	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-02-08	criteria provided, single submitter	clinical testing	The SH3TC2 c.2860C>T variant is classified as PATHOGENIC (PVS1, PS4, PM3, PP1) The SH3TC2 c.2860C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 954 (PVS1). This recurrent variant has been previously reported in both homozygous state or as compound heterozygotes with another pathogenic variant in SH3TC2 in patients with CMT4C (PMID:14574644, 20220177) (PS4, PM3). This variant has been reported to co-segregate with disease (PMID:25737037) (PP1). this variant has been reported in dbSNP (rs80338933) and has been reported in population databases (gnomAD 98/152176, no homozygotes). This variant has been reported in ClinVar as pathogenic for CMT4C by multiple other diagnostic laboratories (ClinVar Variation ID:2482) and is damaging in HGMD for CMT4C (CM033084).
3billion	RCV000002586	SCV002573214	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.073%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002482 / PMID: 14574644 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000002586	SCV002577561	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-02-22	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3, PP5
MGZ Medical Genetics Center	RCV000002586	SCV002581155	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002586	SCV004021208	pathogenic	Charcot-Marie-Tooth disease type 4C	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: SH3TC2 c.2860C>T (p.Arg954X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00075 in 251330 control chromosomes. c.2860C>T has been reported in the literature in many individuals affected with Charcot-Marie Disease Type 4C (e.g. Kontogeorgiou_2019), including individuals who were reported as compound heterozygous with another pathogenic variant. These report(s) suggest the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30653784). 24 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255213	SCV005198229	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002586	SCV005397997	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, type 4C (CMT) (MIM#601596). The mechanism of disease for mild mononeuropathy of the median nerve (MIM#613353) is unknown however, gain of function has been suggested (PMID: 20220177). (I) 0108 - This gene is associated with both recessive and dominant disease. CMT is caused by biallelic variants, while autosomal dominant mild mononeuropathy of the median nerve is rare and has been reported in one family (OMIM, PMID: 20220177). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (206 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported in patients with neuromuscular disease (DECIPHER, PMID: 32153140). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many homozygous and compound heterozygous patients with CMT, or rarely with a demyelinating neuropathy with hearing loss (ClinVar, PMID: 31393079). This variant has also been reported in several heterozygous carriers with very mild median nerve mononeuropathy, however more evidence is required to establish this genotype-phenotype association (PMID: 20220177). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000002586	SCV000022744	pathogenic	Charcot-Marie-Tooth disease type 4C	2010-04-01	no assertion criteria provided	literature only
OMIM	RCV000002587	SCV000022745	pathogenic	Susceptibility to mononeuropathy of the median nerve, mild	2010-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000002586	SCV000041492	not provided	Charcot-Marie-Tooth disease type 4C		no assertion provided	literature only
Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	RCV000144877	SCV000172149	pathogenic	Charcot-Marie-Tooth disease	2013-11-01	no assertion criteria provided	research	Observed in four sporadic individuals
GenomeConnect - Invitae Patient Insights Network	RCV000002586	SCV001749922	not provided	Charcot-Marie-Tooth disease type 4C		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genomics England Pilot Project, Genomics England	RCV000002586	SCV001760156	pathogenic	Charcot-Marie-Tooth disease type 4C		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000255213	SCV001921051	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255213	SCV001932585	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255213	SCV001953960	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255213	SCV001971522	pathogenic	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001851586	SCV002106407	pathogenic	Tip-toe gait	2021-10-26	flagged submission	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV000282937	SCV004765919	pathogenic	SH3TC2-related disorder	2023-12-26	no assertion criteria provided	clinical testing	The SH3TC2 c.2860C>T variant is predicted to result in premature protein termination (p.Arg954*). This variant has been reported in the compound heterozygous and homozygous state to be causative for Charcot-Marie-Tooth disease (Baets et al. 2011. PubMed ID: 21840889; Høyer et al. 2014. PubMed ID: 25025039; Lupski et al. 2010. PubMed ID: 20220177). Although individuals heterozygous for the c.2860C>T (p.Arg954*) variant did not have Charcot-Marie-Tooth disease, they were reported to be at increased risk for developing neuropathy including carpal tunnel syndrome (Lupski et al. 2010. PubMed ID: 20220177). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in SH3TC2 are expected to be pathogenic. This variant is interpreted as pathogenic.