ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.3325C>T (p.Arg1109Ter) (rs80338934)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000002588 SCV000255844 pathogenic Charcot-Marie-Tooth disease, type 4C 2012-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000218266 SCV000279398 pathogenic not provided 2016-05-24 criteria provided, single submitter clinical testing The R1109X nonsense variant has been reported previously in association with CMT4C, and it is a founder mutation in the Spanish gypsy population (Gooding et al., 2005; Claramunt et al., 2007; Sevilla et al., 2013). The R1109X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
GeneReviews RCV000002588 SCV000041494 pathologic Charcot-Marie-Tooth disease, type 4C 2008-03-31 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000654100 SCV000775990 pathogenic Charcot-Marie-Tooth disease type 4 2018-05-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1109*) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80338934, ExAC 0.02%). This variant has been reported in the homozygous state and in the compound heterozygous state with a second SH3TC2 variant in individuals affected with Charcot-Marie-Tooth disease, type 4C (CMT4C) (PMID: 16326826, 22978647, 27231023, 26752306). It has also been reported to segregate with CMT4C in several families and is considered a founder mutation for individuals of Spanish Gypsy ancestry (PMID: 16326826, 17470135). Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000002588 SCV000967788 pathogenic Charcot-Marie-Tooth disease, type 4C 2018-10-10 criteria provided, single submitter clinical testing The p.Arg1109X variant in SH3TC2 has been reported in more than 10 individuals w ith Charcot-Marie-Tooth disease type 4C and segregated with disease in 16 affect ed family members from families (Gooding 2005, Colomer 2006, Claramunt 2007, Sev illa 2013, Piscosquito 2016, Lupo 2016, Khadilkar 2017, Yuan 2018). It has been shown to be a founder mutation in the Spanish Gypsy population (Gooding 2005, Cl aramunt 2007). It has also been identified in 0.02% (7/30778) of South Asian chr omosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant lea ds to a premature termination codon at position 1109, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease ty pe 4C based on case observations, segregation studies, and predicted impact on p rotein. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong.
OMIM RCV000002588 SCV000022746 pathogenic Charcot-Marie-Tooth disease, type 4C 2007-04-01 no assertion criteria provided literature only

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.