ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.2860C>T (p.Arg954Ter) (rs80338933)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Athena Diagnostics Inc RCV000002586 SCV000255843 pathogenic Charcot-Marie-Tooth disease, type 4C 2015-03-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255213 SCV000615245 pathogenic not provided 2015-03-18 criteria provided, single submitter clinical testing
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255213 SCV000339051 pathogenic not provided 2017-04-19 criteria provided, single submitter clinical testing
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
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.
GeneReviews RCV000002586 SCV000041492 pathologic Charcot-Marie-Tooth disease, type 4C 2008-03-31 no assertion criteria provided curation Converted during submission to Pathogenic.
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.
Invitae RCV000168436 SCV000219133 pathogenic Charcot-Marie-Tooth disease type 4 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 954 (p.Arg954*). It is expected to result in an absent or disrupted protein product. This nonsense 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). For these reasons, this variant has been 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
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
UCLA Clinical Genomics Center, UCLA RCV000002586 SCV000255465 pathogenic Charcot-Marie-Tooth disease, type 4C 2014-04-15 criteria provided, single submitter clinical testing

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