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

gnomAD frequency: 0.00003  dbSNP: rs80338934

Total submissions: 19

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	2022-01-18	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: 29321516, 30373780, 30653784, 17470135, 22978647, 25525159, 20301514, 16326826, 31634715, 31127727, 31589614, 32376792)
Invitae	RCV000654100	SCV000775990	pathogenic	Charcot-Marie-Tooth disease type 4	2023-12-23	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. Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs80338934, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Charcot-Marie-Tooth disease, type 4C (CMT4C) (PMID: 16326826, 17470135, 22978647, 26752306, 27231023). It is commonly reported in individuals of Spanish ancestry (PMID: 16326826, 17470135). ClinVar contains an entry for this variant (Variation ID: 2483). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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.
CeGaT Center for Human Genetics Tuebingen	RCV000218266	SCV001249576	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000857137	SCV001335895	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000002588	SCV002577562	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-02-22	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3, PP5
Fulgent Genetics, Fulgent Genetics	RCV002496231	SCV002810025	pathogenic	Charcot-Marie-Tooth disease type 4C; Susceptibility to mononeuropathy of the median nerve, mild	2021-12-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000218266	SCV003827908	pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing
3billion	RCV000002588	SCV003842077	pathogenic	Charcot-Marie-Tooth disease type 4C	2023-02-23	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: 0.004%). This variant was 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. It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 16326826). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000002588	SCV003935001	pathogenic	Charcot-Marie-Tooth disease type 4C	2023-06-23	criteria provided, single submitter	clinical testing	The homozygous pathogenic variant c.3325C>T (p.Arg1109*) has been identified in a proband with phenotypic features of motor delay, frequent falls, difficulty in climbing stairs, asymmetry of face, proximal muscle weakness of lower limbs, positive Romberg’s sign. This variant is identified in exon 14 of SH3TC2 gene. Loss of function is a reported mechanism in SH3TC2 with 104 null pathogenic variants. This variant is predicted to cause NMD. Hence, the ACMG criteria of PVS1_very strong is met. The variant is present in 0.0042% in gnomAD (aggregated) database (PM2_moderate). It has been previously reported (PP5_supporting) PMID 16806930.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000002588	SCV004048092	pathogenic	Charcot-Marie-Tooth disease type 4C		criteria provided, single submitter	clinical testing	The c.3325C>T(p.Arg1109Ter) variant has been reported in more than 10 individuals with Charcot-Marie-Tooth disease type 4C and segregated with disease in 16 affected family members from families (Yuan 2018). It has been shown to be a founder mutation in the Spanish Gypsy population (Cl aramunt 2007). This variant has been reported to the ClinVar database as Pathogenic. The variant has been reported in gnomAD database (0.004%) and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. The nucleotide change in SH3TC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons the variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000218266	SCV004226917	pathogenic	not provided	2022-08-04	criteria provided, single submitter	clinical testing	PP1, PM2, PM3, PS4_moderate, PVS1
OMIM	RCV000002588	SCV000022746	pathogenic	Charcot-Marie-Tooth disease type 4C	2007-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000002588	SCV000041494	not provided	Charcot-Marie-Tooth disease type 4C		no assertion provided	literature only
Genesis Genome Database	RCV000857137	SCV000999716	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research
Inherited Neuropathy Consortium	RCV000857137	SCV001190048	likely pathogenic	Charcot-Marie-Tooth disease		no assertion criteria provided	provider interpretation
Clinical Genetics, Academic Medical Center	RCV000218266	SCV001920074	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000218266	SCV001958172	pathogenic	not provided		no assertion criteria provided	clinical testing