TCAP

Chr 17ADAR

titin-cap

Also known as: CMD1N, CMH25, LGMD2G, LGMDR7, T-cap, TELE, telethonin

NCBI Gene: 8557 ENSG00000173991 UniProt: O15273 OMIM: 604488

The protein binds to titin Z1-Z2 domains in cardiac and skeletal muscle sarcomeres and serves as a substrate for titin kinase, functions critical for sarcomere assembly. Mutations cause autosomal recessive limb-girdle muscular dystrophy type 2G and autosomal dominant hypertrophic cardiomyopathy through a predicted gain-of-function mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.952 OMIM phenotypes

Clinical Summary— TCAP

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Gene-Disease Validity (ClinGen)

hypertrophic cardiomyopathy · ADDisputed

Disputed — evidence questions this relationship

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.189

Z-score 1.67

OE 0.30 (0.12–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.09Z-score

OE missense 0.98 (0.83–1.15)

102 obs / 104.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.12–0.95)

0≤0.351.4

Missense OE?0.98 (0.83–1.15)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 2 / 6.6Missense obs/exp: 102 / 104.5Syn Z: -0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedTCAP-related hypertrophic cardiomyopathyOTHERAD

limitedTCAP-related dilated cardiomyopathyOTHERAD

This gene — mechanism propensity

0.6357th %ile

GOF

0.7029th %ile

LOF

0.4135th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

DNprediction above median

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.

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