SH3TC2

protein-coding

SH3 domain and tetratricopeptide repeats 2, the group of MicroRNA protein coding host genes|Tetratricopeptide repeat domain containing

Gene summary

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]

MANE transcript

NM_024577.4

Inheritance

AR, AD

ClinVar variants

P:177U:603B:410

Top phenotype

Charcot-Marie-Tooth disease, type 4C; Mononeuropathy of the median nerve, mild

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr5:148,923,639-149,063,163

External References & Databases

Ensembl (ENSG00000169247)

Transcript & Mutation Effects

hg38 • Region Span ~139.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 4CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011113

Submitter: ClinGen

SH3TC2 was first reported in relation to autosomal recessive hereditary demyelinating motor and sensory neuropathy in 2003 (Senderek et al., PMID:14574644). It is mainly characterized by a sensory-motor demyelinating neuropathy with onset typically in childhood. Early-onset scoliosis is present in a large number of patients. SH3TC2 has been noted to be associated with the following disease entities: Charcot-Marie-Tooth disease, type 4C (OMIM: 601596) and Mononeuropathy of the median nerve, mild (OMIM: 613353). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern AND phenotypic variability. Therefore, the disease entities have been Split. About 80 variants have been reported, including missense and nonsense variants. The maximum score for genetics evidence has been reached (12 points). Evidence supporting the gene-disease relationship includes case-level variant evidence and experimental data. Hela cells transfected with SH3TC2 mutants fail to co-localize with RAB11 at recycling endosomes and co-immunoprecipitation assay confirmed loss of protein-protein interaction with RAB11 in the mutants. SH3TC2 mutants fail to induce membrane receptor internalization in transfected cells compared to wild-type (Gouttenoire et al., PMID: 23553667). Therefore, the mechanism for pathogenicity appears to be loss-of-function. A knockout mouse model for SH3TC2 developed progressive peripheral neuropathy, mimicking the human phenotype (Arnaud et a., PMID: 19805030). Nerve biopsy shows severe hypomyelination in the knockout mice. The mice phenotype was rescued with a lentivirus expressing the human SH3TC2 cDNA, which was delivered intrathecally (Schiza et al., PMID: 30907403). In summary, SH3TC2 is definitively associated with autosomal recessive hereditary demyelinating motor and sensory neuropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

susceptibility to mononeuropathy of the median nerve, mildSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013237

Submitter: PanelApp Australia

susceptibility to mononeuropathy of the median nerve, mildLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013237

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 4CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011113

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 4CSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011113

Submitter: Orphanet

susceptibility to mononeuropathy of the median nerve, mildLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013237

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease type 4CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011113

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, type 4C; Mononeuropathy of the median nerve, mildAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 14574644; 16326826; 16924012; 19744956; 20220177; 20301514; 20301641; 21291453; 22950825

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH3TC2 variants in ClinVar

29 Conditions Cataloged

Charcot-Marie-Tooth disease type 4Total: 1072

not providedTotal: 339

Inborn genetic diseasesTotal: 324

Charcot-Marie-Tooth diseaseTotal: 193

Charcot-Marie-Tooth disease type 4CTotal: 190

SH3TC2-related disorderTotal: 169

not specifiedTotal: 144

Susceptibility to mononeuropathy of the median nerve, mildTotal: 122

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024577.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		5 clinvar	304 clinvar	8 clinvar	318
missense		24 clinvar	578 clinvar	97 clinvar	1 clinvar	700
nonsense	43 clinvar	20 clinvar	4 clinvar			67
start loss		1 clinvar				1
frameshift	41 clinvar	22 clinvar	14 clinvar			77
splice donor/acceptor (+/-2bp)	7 clinvar	18 clinvar	2 clinvar			27
Total	92	85	603	401	9	1190

Highest pathogenic variant AF is 0.0010427419

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024577.4	RefSeq	NP_078853.2	17	MANE Select
ENST00000515425.6	Ensembl	ENSP00000423660.1	17	MANE Select
ENST00000323829.9	Ensembl	ENSP00000313025.5	7	Standard
ENST00000502274.2	Ensembl	ENSP00000421092.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

peripheral nervous system myelin maintenance
regulation of intracellular protein transport
regulation of ERBB signaling pathway

Cellular Component

plasma membrane
cytoplasmic vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000515425
Coding exons: 17
Length: 139525
Individuals with no LoFs: 125451
Homozygous LoFs: 0
Heterozygous LoFs: 297
Defined: 125748
p: 0.00118

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.713	721	669	1.08	0.0000386	8347
Missense (PolyPhen)		188	187.03	1.0052		2425
Synonymous	-1.40	307	277	1.11	0.0000151	2631
Loss of Function	2.67	33	54.3	0.608	0.00000274	663

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00080	0.00080	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00069	0.00069	rare
European (Non-Finnish)	0.0018	0.0018	notable
South Asian	0.0011	0.0011	notable
Other	0.0018	0.0018	notable

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Mononeuropathy of the median nerve mild (MNMN) [MIM:613353]: A disease characterized by median nerve mononeuropathy at the wrist. The clinical presentation ranges from a mild phenotype, consistent with carpal tunnel syndrome, to a severe median nerve mononeuropathy at the wrist associated with evidence of a more widespread axonal polyneuropathy. The latter phenotype is similar to that of patients with hereditary neuropathy with liability to pressure palsies. {ECO:0000269|PubMed:20220177}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.477
RVIS EVS: 0.02
RVIS percentile EVS: 55.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.368

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium