TTN

titin, the group of Fibronectin type III domain containing|I-set domain containing|Myosin light chain kinase family

Basic information

Region (hg38): 2:178525988-178830802

Previous symbols: [ "CMD1G" ]

Links

ENSG00000155657 ∙ NCBI:7273 ∙ OMIM:188840 ∙ HGNC:12403 ∙ Uniprot:Q8WZ42 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• early-onset myopathy with fatal cardiomyopathy (Definitive), mode of inheritance: AR
• hypertrophic cardiomyopathy 9 (Moderate), mode of inheritance: AD
• tibial muscular dystrophy (Moderate), mode of inheritance: AD
• dilated cardiomyopathy 1G (Definitive), mode of inheritance: AD
• autosomal recessive limb-girdle muscular dystrophy type 2J (Moderate), mode of inheritance: AR
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• tibial muscular dystrophy (Supportive), mode of inheritance: AD
• autosomal recessive limb-girdle muscular dystrophy type 2J (Supportive), mode of inheritance: AR
• autosomal recessive centronuclear myopathy (Supportive), mode of inheritance: AR
• myopathy, myofibrillar, 9, with early respiratory failure (Supportive), mode of inheritance: AD
• early-onset myopathy with fatal cardiomyopathy (Supportive), mode of inheritance: AR
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome (Supportive), mode of inheritance: AR
• dilated cardiomyopathy 1G (Definitive), mode of inheritance: AD
• early-onset myopathy with fatal cardiomyopathy (Strong), mode of inheritance: AR
• dilated cardiomyopathy 1G (Strong), mode of inheritance: AD
• hypertrophic cardiomyopathy 9 (Limited), mode of inheritance: AD
• myopathy, myofibrillar, 9, with early respiratory failure (Strong), mode of inheritance: AD
• autosomal recessive limb-girdle muscular dystrophy type 2J (Strong), mode of inheritance: AR
• tibial muscular dystrophy (Strong), mode of inheritance: AD
• myopathy, myofibrillar, 9, with early respiratory failure (Moderate), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD
• TTN-related myopathy (Definitive), mode of inheritance: AR
• arrhythmogenic right ventricular cardiomyopathy (Limited), mode of inheritance: AD
• myopathy, myofibrillar, 9, with early respiratory failure (Moderate), mode of inheritance: AD
• hypertrophic cardiomyopathy (Limited), mode of inheritance: AD
• tibial muscular dystrophy (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, familial hypertrophic 9; Cardiomyopathy, dilated, 1G; Congenital myopathy 5 with cardiomyopathy	AD/AR	Cardiovascular	Surveillance (including with echocardiography) may allow early detection and treatment, (including with interventions such as left ventricular assist device), and preventive measures may be additionally beneficial; Heart transplantation has been described for some conditions related to variants in TTN	Cardiovascular; Musculoskeletal	4855680; 126303; 196233; 6251174; 1619633; 1487757; 10053013; 10462489; 11788824; 12145747; 11846417; 12891679; 15802564; 17444505; 20627570; 22335739; 22577215; 22475360; 24105469
Some allelic conditions have been reported as potentially including cardiovascular anomalies, but it is unclear if molecular diagnosis was uniformly verified

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TTN gene.

• not provided (10666 variants)
• Dilated cardiomyopathy 1G;Autosomal recessive limb-girdle muscular dystrophy type 2J (10270 variants)
• Cardiovascular phenotype (6452 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2J;Dilated cardiomyopathy 1G (6110 variants)
• not specified (5466 variants)
• Early-onset myopathy with fatal cardiomyopathy (2212 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2J (2204 variants)
• Tibial muscular dystrophy (2196 variants)
• Myopathy, myofibrillar, 9, with early respiratory failure (2191 variants)
• Cardiomyopathy (2107 variants)
• Dilated cardiomyopathy 1G (2038 variants)
• 6 conditions (1304 variants)
• Primary dilated cardiomyopathy (465 variants)
• TTN-related condition (257 variants)
• Hypertrophic cardiomyopathy (129 variants)
• Tip-toe gait (63 variants)
• Dilated cardiomyopathy 1G;Hypertrophic cardiomyopathy 9 (52 variants)
• Hypertrophic cardiomyopathy 9 (51 variants)
• Primary familial dilated cardiomyopathy (47 variants)
• Limb-Girdle Muscular Dystrophy, Recessive (41 variants)
• Dilated Cardiomyopathy, Dominant (40 variants)
• TTN-Related Disorders (40 variants)
• Hypertrophic cardiomyopathy 9;Dilated cardiomyopathy 1G (37 variants)
• Inborn genetic diseases (36 variants)
• See cases (20 variants)
• Primary familial hypertrophic cardiomyopathy (16 variants)
• Arrhythmogenic right ventricular cardiomyopathy (15 variants)
• Dilated cardiomyopathy 1A (15 variants)
• Left ventricular noncompaction cardiomyopathy (14 variants)
• Brugada syndrome (13 variants)
• Long QT syndrome (12 variants)
• TTN-related myopathy (12 variants)
• Ventricular tachycardia (11 variants)
• Dilated cardiomyopathy 1S (10 variants)
• Myopathy (9 variants)
• - (8 variants)
• Atrial fibrillation (8 variants)
• TTN-related disease (7 variants)
• SUDDEN INFANT DEATH SYNDROME (5 variants)
• Abnormality of neuronal migration (4 variants)
• Heart failure (4 variants)
• Left ventricular hypertrophy (4 variants)
• Centronuclear myopathy (4 variants)
• Ventricular fibrillation (3 variants)
• Supraventricular tachycardia (3 variants)
• Familial restrictive cardiomyopathy (3 variants)
• Ventricular tachycardia;Cardiomyopathy (3 variants)
• Arrhythmogenic right ventricular dysplasia 1 (3 variants)
• Left ventricular noncompaction 2 (3 variants)
• Arrhythmogenic right ventricular dysplasia 9 (3 variants)
• Ventricular fibrillation;Cardiomyopathy (3 variants)
• Multiminicore myopathy (3 variants)
• Premature ventricular contraction (3 variants)
• Primary dilated cardiomyopathy;Cardiomyopathy (3 variants)
• Sudden cardiac arrest (3 variants)
• Desmin-related myofibrillar myopathy (3 variants)
• Long QT syndrome;Cardiomyopathy (2 variants)
• Third degree atrioventricular block (2 variants)
• Hypertrophic cardiomyopathy;Supraventricular tachycardia (2 variants)
• Hypertrophic cardiomyopathy;Cardiomyopathy (2 variants)
• Amyloidogenic transthyretin amyloidosis (2 variants)
• Heart failure;Long QT syndrome;Cardiomyopathy (2 variants)
• Congenital titinopathy (2 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2J;Early-onset myopathy with fatal cardiomyopathy (2 variants)
• Limb-girdle muscular dystrophy (2 variants)
• TTN-Related disorder (2 variants)
• Congestive heart failure (2 variants)
• Muscular dystrophy (2 variants)
• Rare genetic intellectual disability (2 variants)
• Hypertrophic cardiomyopathy;Cardiomyopathy;Congestive heart failure (1 variants)
• Atrial fibrillation;Cardiomyopathy (1 variants)
• 7 conditions (1 variants)
• Early-onset myopathy with fatal cardiomyopathy;Congenital titinopathy (1 variants)
• Ventricular tachycardia;Atrial fibrillation (1 variants)
• Interstitial cardiac fibrosis (1 variants)
• Myopathy, myofibrillar, 9, with early respiratory failure;Autosomal recessive limb-girdle muscular dystrophy type 2J;Tibial muscular dystrophy;Primary dilated cardiomyopathy;Autosomal recessive centronuclear myopathy (1 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2J;Tibial muscular dystrophy;Myopathy, myofibrillar, 9, with early respiratory failure;Primary dilated cardiomyopathy (1 variants)
• Tibial muscular dystrophy;Autosomal recessive limb-girdle muscular dystrophy type 2J;Primary dilated cardiomyopathy (1 variants)
• Dilated cardiomyopathy 1G;Hypertrophic cardiomyopathy 9;Autosomal recessive limb-girdle muscular dystrophy type 2J (1 variants)
• Dilated cardiomyopathy 1G;Early-onset myopathy with fatal cardiomyopathy;Hypertrophic cardiomyopathy 9;Autosomal recessive limb-girdle muscular dystrophy type 2J (1 variants)
• Dilated cardiomyopathy 1G;Early-onset myopathy with fatal cardiomyopathy;Hypertrophic cardiomyopathy 9;Autosomal recessive limb-girdle muscular dystrophy type 2J;Myopathy, myofibrillar, 9, with early respiratory failure (1 variants)
• Primary dilated cardiomyopathy;Myopathy, myofibrillar, 9, with early respiratory failure;Autosomal recessive limb-girdle muscular dystrophy type 2J;Tibial muscular dystrophy (1 variants)
• Myopathy, myofibrillar, 9, with early respiratory failure;Primary dilated cardiomyopathy;Autosomal recessive limb-girdle muscular dystrophy type 2J;Tibial muscular dystrophy (1 variants)
• Hypertrophic cardiomyopathy 1 (1 variants)
• Cardiomyopathy;Long QT syndrome (1 variants)
• Myopathy, myofibrillar, 9, with early respiratory failure;Tibial muscular dystrophy;Autosomal recessive limb-girdle muscular dystrophy type 2J;Primary dilated cardiomyopathy (1 variants)
• Dilated cardiomyopathy 1G;Tibial muscular dystrophy;Myopathy, myofibrillar, 9, with early respiratory failure;Autosomal recessive limb-girdle muscular dystrophy type 2J;Hypertrophic cardiomyopathy 9 (1 variants)
• Wolff-Parkinson-White pattern (1 variants)
• Primary dilated cardiomyopathy;Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Hypertrophic cardiomyopathy 9;Tibial muscular dystrophy;Myopathy, myofibrillar, 9, with early respiratory failure;Dilated cardiomyopathy 1G (1 variants)
• Lower limb muscle weakness (1 variants)
• Cerebral palsy (1 variants)
• Autosomal recessive titinopathy (1 variants)
• CAP-congenital myopathy with arthrogryposis multiplex congenita without heart involvement (1 variants)
• Tibial muscular dystrophy;Autosomal recessive limb-girdle muscular dystrophy type 2J (1 variants)
• 8 conditions (1 variants)
• Primary dilated cardiomyopathy;Heart failure (1 variants)
• Abnormality of the musculature (1 variants)
• Systolic heart failure (1 variants)
• Primary dilated cardiomyopathy;Cardiomyopathy;Noncompaction cardiomyopathy;Low-output congestive heart failure (1 variants)
• Myopathy;Rimmed vacuoles;Lower limb muscle weakness (1 variants)
• Primary dilated cardiomyopathy;Arrhythmogenic right ventricular cardiomyopathy;Atrial fibrillation (1 variants)
• Proximal lower limb amyotrophy;Decreased patellar reflex;Limb-girdle muscular dystrophy;Muscular dystrophy;Waddling gait (1 variants)
• Hypertrophic cardiomyopathy;Ventricular tachycardia;Cardiomyopathy (1 variants)
• Cardiomyopathy;Brugada syndrome (1 variants)
• Cardiomyopathy;Primary dilated cardiomyopathy (1 variants)
• Limb-girdle muscle weakness;Limb-girdle muscle atrophy (1 variants)
• Early-onset myopathy with fatal cardiomyopathy;Autosomal recessive limb-girdle muscular dystrophy type 2J (1 variants)
• Minicore myopathy (1 variants)
• Myopathy, myofibrillar, 9, with early respiratory failure;Dilated cardiomyopathy 1G;Early-onset myopathy with fatal cardiomyopathy;Hypertrophic cardiomyopathy 9 (1 variants)
• Primary dilated cardiomyopathy;Myopathy, centronuclear, 2;Autosomal recessive limb-girdle muscular dystrophy type 2J;Tibial muscular dystrophy;Myopathy, myofibrillar, 9, with early respiratory failure (1 variants)
• Primary dilated cardiomyopathy;Atrial fibrillation (1 variants)
• Orofacial cleft 1 (1 variants)
• Atrial fibrillation;Ventricular tachycardia;Congestive heart failure (1 variants)
• Decreased patellar reflex;Proximal lower limb amyotrophy;Waddling gait;Muscular dystrophy;Limb-girdle muscular dystrophy (1 variants)
• Syncope;Hypertrophic cardiomyopathy (1 variants)
• Hypertrophic cardiomyopathy 9;Autosomal recessive limb-girdle muscular dystrophy type 2J;Early-onset myopathy with fatal cardiomyopathy;Dilated cardiomyopathy 1G (1 variants)
• Dilated cardiomyopathy 1G;Autosomal recessive limb-girdle muscular dystrophy type 2J;Hypertrophic cardiomyopathy 9;Myopathy, myofibrillar, 9, with early respiratory failure;Tibial muscular dystrophy (1 variants)
• Noncompaction cardiomyopathy (1 variants)
• Hypertrophic cardiomyopathy;Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Left ventricular noncompaction (1 variants)
• Reduced left ventricular ejection fraction;Noncompaction cardiomyopathy (1 variants)
• Hypertrophic cardiomyopathy;Ventricular tachycardia;Familial dilated cardiomyopathy and peripheral neuropathy (1 variants)
• Congenital myopathy (1 variants)
• X-linked myopathy with postural muscle atrophy (1 variants)
• Fatty replacement of skeletal muscle;Late-onset muscular dystrophy;Gait disturbance;Muscular dystrophy;EMG abnormality (1 variants)
• Sudden cardiac death;Cardiac arrest (1 variants)
• Heart failure;Primary dilated cardiomyopathy (1 variants)
• Supraventricular tachycardia;Ventricular tachycardia;Brugada syndrome (1 variants)
• Primary dilated cardiomyopathy;Brugada syndrome (1 variants)
• Neuromuscular disease (1 variants)
• Ventricular fibrillation, paroxysmal familial, type 1 (1 variants)
• Restrictive cardiomyopathy (1 variants)
• Dilated cardiomyopathy 1G;Hypertrophic cardiomyopathy 9;Myopathy, myofibrillar, 9, with early respiratory failure (1 variants)
• Neurodevelopmental delay (1 variants)
• Right ventricular cardiomyopathy (1 variants)
• Hypertrophic cardiomyopathy;Cardiomyopathy;Long QT syndrome (1 variants)
• Primary dilated cardiomyopathy;Autosomal recessive limb-girdle muscular dystrophy type 2J;Myopathy, myofibrillar, 9, with early respiratory failure;Tibial muscular dystrophy (1 variants)
• Dilated cardiomyopathy 1G;Tibial muscular dystrophy;Myopathy, myofibrillar, 9, with early respiratory failure;Hypertrophic cardiomyopathy 9 (1 variants)
• Motor delay (1 variants)
• Restrictive ventilatory defect;Bilateral talipes equinovarus;Areflexia of lower limbs;Thoracic kyphoscoliosis;Spinal rigidity (1 variants)
• Thoracic kyphoscoliosis;Spinal rigidity;Bilateral talipes equinovarus;Restrictive ventilatory defect;Areflexia of lower limbs (1 variants)
• Supraventricular tachycardia;Cardiomyopathy (1 variants)
• Conduction disorder of the heart (1 variants)
• Hypertrophic cardiomyopathy;Atrial fibrillation;Brugada syndrome;Congestive heart failure (1 variants)
• Mitral valve prolapse (1 variants)
• Primary dilated cardiomyopathy;Myocarditis (1 variants)
• Family history of cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TTN gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			226	7280	81	7587
missense	4	21	8670	866	55	9616
nonsense	72	870	283		1	1226
start loss						0
frameshift	94	1362	422			1878
inframe indel	1	4	206	5		216
splice donor/acceptor (+/-2bp)	18	151	245	1		415
splice region		3	347	506	20	876
non coding		1	79	1668	302	2050
Total	189	2409	10131	9820	439

Highest pathogenic variant AF is 0.0000263

Variants in TTN

This is a list of pathogenic ClinVar variants found in the TTN region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-178525997-T-C		Dilated cardiomyopathy 1G • Tibial muscular dystrophy • Autosomal recessive limb-girdle muscular dystrophy type 2J • Myopathy, myofibrillar, 9, with early respiratory failure • Early-onset myopathy with fatal cardiomyopathy	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-178526044-A-G		Myopathy, myofibrillar, 9, with early respiratory failure • Autosomal recessive limb-girdle muscular dystrophy type 2J • Dilated cardiomyopathy 1G • Tibial muscular dystrophy • Early-onset myopathy with fatal cardiomyopathy	Uncertain significance (Jan 13, 2018)
2-178526093-C-G		Dilated cardiomyopathy 1G • Early-onset myopathy with fatal cardiomyopathy • Myopathy, myofibrillar, 9, with early respiratory failure • Autosomal recessive limb-girdle muscular dystrophy type 2J • Tibial muscular dystrophy	Uncertain significance (Jan 13, 2018)
2-178526099-G-T		Autosomal recessive limb-girdle muscular dystrophy type 2J • Tibial muscular dystrophy • Early-onset myopathy with fatal cardiomyopathy • Myopathy, myofibrillar, 9, with early respiratory failure • Dilated cardiomyopathy 1G • 6 conditions	Uncertain significance (Oct 19, 2021)
2-178526114-T-G		Myopathy, myofibrillar, 9, with early respiratory failure • Autosomal recessive limb-girdle muscular dystrophy type 2J • Early-onset myopathy with fatal cardiomyopathy • Dilated cardiomyopathy 1G • Tibial muscular dystrophy	Uncertain significance (Jan 12, 2018)
2-178526348-C-A		Tibial muscular dystrophy • Early-onset myopathy with fatal cardiomyopathy • Autosomal recessive limb-girdle muscular dystrophy type 2J • Dilated cardiomyopathy 1G • Myopathy, myofibrillar, 9, with early respiratory failure	Benign/Likely benign (May 23, 2021)
2-178526376-A-C		Dilated cardiomyopathy 1G • Tibial muscular dystrophy • Early-onset myopathy with fatal cardiomyopathy • Myopathy, myofibrillar, 9, with early respiratory failure • Autosomal recessive limb-girdle muscular dystrophy type 2J	Uncertain significance (Jan 13, 2018)
2-178526379-G-A		Tibial muscular dystrophy • Myopathy, myofibrillar, 9, with early respiratory failure • Dilated cardiomyopathy 1G • Early-onset myopathy with fatal cardiomyopathy • Autosomal recessive limb-girdle muscular dystrophy type 2J	Uncertain significance (Mar 16, 2018)
2-178526389-C-T		Myopathy, myofibrillar, 9, with early respiratory failure • Early-onset myopathy with fatal cardiomyopathy • Dilated cardiomyopathy 1G • Autosomal recessive limb-girdle muscular dystrophy type 2J • Tibial muscular dystrophy	Uncertain significance (Jan 12, 2018)
2-178526425-A-T		Dilated cardiomyopathy 1G • Myopathy, myofibrillar, 9, with early respiratory failure • Early-onset myopathy with fatal cardiomyopathy • Tibial muscular dystrophy • Autosomal recessive limb-girdle muscular dystrophy type 2J	Conflicting classifications of pathogenicity (May 25, 2021)
2-178526508-C-T		Tibial muscular dystrophy • Myopathy, myofibrillar, 9, with early respiratory failure • Autosomal recessive limb-girdle muscular dystrophy type 2J • Early-onset myopathy with fatal cardiomyopathy • Dilated cardiomyopathy 1G	Uncertain significance (Jan 12, 2018)
2-178526732-T-C		Myopathy, myofibrillar, 9, with early respiratory failure • Early-onset myopathy with fatal cardiomyopathy • Tibial muscular dystrophy • Dilated cardiomyopathy 1G • Autosomal recessive limb-girdle muscular dystrophy type 2J	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-178526738-C-T		Autosomal recessive limb-girdle muscular dystrophy type 2J • Early-onset myopathy with fatal cardiomyopathy • Tibial muscular dystrophy • Myopathy, myofibrillar, 9, with early respiratory failure • Dilated cardiomyopathy 1G	Uncertain significance (Jan 13, 2018)
2-178526815-G-C		Early-onset myopathy with fatal cardiomyopathy • Autosomal recessive limb-girdle muscular dystrophy type 2J • Tibial muscular dystrophy • Myopathy, myofibrillar, 9, with early respiratory failure • Dilated cardiomyopathy 1G	Uncertain significance (Jan 13, 2018)
2-178526829-T-C		Early-onset myopathy with fatal cardiomyopathy • Autosomal recessive limb-girdle muscular dystrophy type 2J • Tibial muscular dystrophy • Dilated cardiomyopathy 1G • Myopathy, myofibrillar, 9, with early respiratory failure	Uncertain significance (Jan 12, 2018)
2-178526871-A-C		Dilated cardiomyopathy 1G • Myopathy, myofibrillar, 9, with early respiratory failure • Tibial muscular dystrophy • Autosomal recessive limb-girdle muscular dystrophy type 2J • Early-onset myopathy with fatal cardiomyopathy • 6 conditions	Uncertain significance (Dec 06, 2021)
2-178526882-C-G		Tibial muscular dystrophy • Autosomal recessive limb-girdle muscular dystrophy type 2J • Dilated cardiomyopathy 1G • Myopathy, myofibrillar, 9, with early respiratory failure • Early-onset myopathy with fatal cardiomyopathy	Benign/Likely benign (Jan 13, 2018)
2-178526912-CT-C			Likely benign (Jun 26, 2018)
2-178526912-C-CT		Limb-Girdle Muscular Dystrophy, Recessive • Hypertrophic cardiomyopathy • Myopathy, myofibrillar, 9, with early respiratory failure • Early-onset myopathy with fatal cardiomyopathy • Dilated Cardiomyopathy, Dominant • Tibial muscular dystrophy • Autosomal recessive limb-girdle muscular dystrophy type 2J	Benign/Likely benign (Sep 10, 2021)
2-178526953-C-T		Dilated cardiomyopathy 1G • Early-onset myopathy with fatal cardiomyopathy • Tibial muscular dystrophy • Myopathy, myofibrillar, 9, with early respiratory failure • Autosomal recessive limb-girdle muscular dystrophy type 2J	Conflicting classifications of pathogenicity (Jan 12, 2018)
2-178526969-G-A			Likely benign (Jul 14, 2018)
2-178526987-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2J • Tibial muscular dystrophy • Early-onset myopathy with fatal cardiomyopathy • Myopathy, myofibrillar, 9, with early respiratory failure • Dilated cardiomyopathy 1G	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-178527006-G-T		Early-onset myopathy with fatal cardiomyopathy • Tibial muscular dystrophy • Myopathy, myofibrillar, 9, with early respiratory failure • Dilated cardiomyopathy 1G • Autosomal recessive limb-girdle muscular dystrophy type 2J • not specified	Conflicting classifications of pathogenicity (Mar 17, 2020)
2-178527013-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2J;Dilated cardiomyopathy 1G	Likely benign (Feb 19, 2021)
2-178527014-A-G			Uncertain significance (Nov 05, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TTN	protein_coding	protein_coding	ENST00000589042	362	304814

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.56e-96	1.00	124166	4	1578	125748	0.00631

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.10	18060	1.76e+4	1.02	0.000987	233777
Missense in Polyphen
Synonymous	-0.166	6427	6.41e+3	1.00	0.000367	72068
Loss of Function	22.8	435	1.33e+3	0.327	0.0000763	18944

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0278	0.0254
Ashkenazi Jewish	0.00429	0.00428
East Asian	0.00544	0.00529
Finnish	0.00310	0.00296
European (Non-Finnish)	0.00601	0.00576
Middle Eastern	0.00544	0.00529
South Asian	0.00607	0.00570
Other	0.00589	0.00572

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase. {ECO:0000269|PubMed:9804419}.
• Disease: DISEASE: Hereditary myopathy with early respiratory failure (HMERF) [MIM:603689]: Autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. {ECO:0000269|PubMed:15802564}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 9 (CMH9) [MIM:613765]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:10462489}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1G (CMD1G) [MIM:604145]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:11788824, ECO:0000269|PubMed:11846417, ECO:0000269|PubMed:16465475}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tardive tibial muscular dystrophy (TMD) [MIM:600334]: Autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later. {ECO:0000269|PubMed:12145747, ECO:0000269|PubMed:12891679}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Limb-girdle muscular dystrophy 2J (LGMD2J) [MIM:608807]: An autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. {ECO:0000269|PubMed:12145747}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Salih myopathy (SALMY) [MIM:611705]: An autosomal recessive, early-onset muscular disorder characterized by dilated cardiomyopathy, delayed motor development with generalized muscle weakness predominantly affecting proximal and distal lower limbs. Skeletal muscle biopsies show minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes become apparent in the second decade. Cardiac muscle biopsies show disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. Sudden death may occurr due to cardiomyopathy. {ECO:0000269|PubMed:17444505}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Dilated cardiomyopathy (DCM) - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Striated Muscle Contraction;Striated Muscle Contraction;Muscle contraction;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Hemostasis (Consensus)

Recessive Scores

• pRec: 0.384

Intolerance Scores

• loftool: 0.971
• rvis_EVS: 2.17
• rvis_percentile_EVS: 98.04

Haploinsufficiency Scores

• pHI: 0.407
• hipred: N
• hipred_score: 0.414
• ghis: 0.505

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.949

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Ttn
• Phenotype: growth/size/body region phenotype; muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; skeleton phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: ttn.1
• Affected structure: skeletal muscle cell
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: platelet degranulation;cardiac muscle hypertrophy;muscle contraction;striated muscle contraction;mitotic chromosome condensation;positive regulation of gene expression;protein kinase A signaling;peptidyl-tyrosine phosphorylation;muscle filament sliding;skeletal muscle thin filament assembly;skeletal muscle myosin thick filament assembly;detection of muscle stretch;sarcomere organization;regulation of protein kinase activity;cardiac muscle fiber development;sarcomerogenesis;positive regulation of protein secretion;regulation of catalytic activity;response to calcium ion;cardiac myofibril assembly;cardiac muscle tissue morphogenesis;cardiac muscle contraction;striated muscle myosin thick filament assembly
• Cellular component: condensed nuclear chromosome;extracellular region;cytosol;striated muscle thin filament;sarcomere;Z disc;M band;I band;extracellular exosome
• Molecular function: protease binding;protein serine/threonine kinase activity;protein tyrosine kinase activity;calcium ion binding;protein binding;calmodulin binding;ATP binding;structural constituent of muscle;enzyme binding;protein kinase binding;telethonin binding;identical protein binding;actinin binding;protein self-association;actin filament binding;muscle alpha-actinin binding;structural molecule activity conferring elasticity