Submissions for variant NM_024577.4(SH3TC2):c.3325C>T (p.Arg1109Ter) (rs80338934)

Total submissions: 7

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.
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
GeneReviews	RCV000002588	SCV000041494	pathologic	Charcot-Marie-Tooth disease, type 4C	2008-03-31	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Genesis Genome Database	RCV000857137	SCV000999716	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research