SH3TC2

Chr 5ARAD

SH3 domain and tetratricopeptide repeats 2

Also known as: CMT4C, MNMN

NCBI Gene: 79628 ENSG00000169247 UniProt: Q8TF17 OMIM: 608206

This gene encodes an adapter protein containing two SH3 domains and 10 tetratricopeptide repeat motifs that localizes to the cell membrane. Mutations cause autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disorder characterized by demyelination of motor and sensory neurons, and can also cause mild median nerve mononeuropathy with autosomal dominant inheritance. The pathogenic mechanism appears to involve gain-of-function effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismAR/ADLOEUF 0.812 OMIM phenotypes

Clinical Summary— SH3TC2

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Gene-Disease Validity (ClinGen)

obsolete autosomal recessive hereditary demyelinating motor and sensory neuropathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.81LOEUF

pLI 0.000

Z-score 2.67

OE 0.61 (0.46–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

-0.71Z-score

OE missense 1.08 (1.01–1.15)

721 obs / 669.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.61 (0.46–0.81)

0≤0.351.4

Missense OE1.08 (1.01–1.15)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 33 / 54.3Missense obs/exp: 721 / 669.1Syn Z: -1.40

0.6162th %ile

GOF

0.72top 25%

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNConsistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro.PMID:20826437

GOFThese findings of axonal neuropathy (Table 1) suggest a gain of function (i.e., a toxic effect) of this mutation.PMID:20220177

LOFWe observed that both of the SH3TC2 mutations, when heterozygous, have phenotypic consequences that can be detected by electrophysiological means. The Y169H missense variant segregates with an axonal neuropathy, whereas the nonsense R954X mutation is associated with subclinical evidence of the carpaPMID:20220177

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.