rs80338933

chr5-149026872-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024577.4(SH3TC2):c.2860C>T(p.Arg954Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: SH3TC2 NM_024577.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36 O:2
• Conservation: PhyloP100: 2.63

Genes affected

SH3TC2 (HGNC:29427): (SH3 domain and tetratricopeptide repeats 2) This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-149026872-G-A is Pathogenic according to our data. Variant chr5-149026872-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149026872-G-A is described in Lovd as [Pathogenic]. Variant chr5-149026872-G-A is described in Lovd as [Likely_pathogenic]. Variant chr5-149026872-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.2860C>T	p.Arg954Ter	stop_gained	11/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.2860C>T	p.Arg954Ter	stop_gained	11/17	1	NM_024577.4	P2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000748 AC: 188 AN: 251330 Hom.: 0 AF XY: 0.000847 AC XY: 115 AN XY: 135842

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00108 AC: 1585 AN: 1461838 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 781 AN XY: 727218

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74346

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000601

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00136

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:36 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 07, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2018	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.). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SH3TC2: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 21, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2021	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) -

Charcot-Marie-Tooth disease type 4C Pathogenic:11 Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Apr 15, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 22, 2022	PVS1, PM2, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 08, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -

Charcot-Marie-Tooth disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Pathogenic, no assertion criteria provided	research	Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	Nov 01, 2013	Observed in four sporadic individuals -

SH3TC2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 20, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 26, 2023	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

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. -

Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

Tip-toe gait Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Oct 26, 2021

- -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.53	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.82
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338933; hg19: chr5-148406435; COSMIC: COSV60460740; COSMIC: COSV60460740;