TTC19

protein-coding

tetratricopeptide repeat domain 19, the group of Mitochondrial respiratory chain complex assembly factors|Tetratricopeptide repeat domain containing

Gene summary

This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2012]

MANE transcript

NM_017775.4

Inheritance

ClinVar variants

P:33U:118B:66

Top phenotype

Mitochondrial complex III deficiency, nuclear type 2

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr17:15,999,784-16,045,015

External References & Databases

Ensembl (ENSG00000011295)

Transcript & Mutation Effects

hg38 • Region Span ~45.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TTC19* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 22, 2024. *TTC19* encodes tetratricopeptide repeat domain-containing protein 19, an assembly factor critical for assembly of complex III of the mitochondrial respiratory chain. *TTC19* was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID: 21278747). While various names have been given to the constellation of features seen in those with *TTC19*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TTC19* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *TTC19* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP V6), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three nonsense variants and two frameshift variants in six probands from four publications (PMIDs: 21278747, 24397319, 25652355, 37927170). There are additional cases reported in the medical literature; however, these were not included in this curation as the maximum genetic evidence score was reached. Age of onset varies from early in life to adulthood. Clinical features in affected individuals include LSS, global developmental delay, developmental regression, ataxia, dysarthria, seizures, neuropathy, myopathy, psychiatric involvement, hearing loss, and lactic acidosis. Complex III deficiency is seen in biopsied skeletal muscle. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of TTC19 in complex III assembly, functional alteration in patient cells, a mouse model, and a fruit fly model (PMIDs: 21278747, 28673544). In summary, there is definitive evidence to support the relationship between *TTC19* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 22, 2024 (SOP Version 10).

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

mitochondrial complex III deficiency nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014063

Submitter: PanelApp Australia

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between TTC19 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2019. Variants in TTC19 were first reported in humans with Leigh syndrome spectrum as early as 2011 (PMID: 21278747). More than 10 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight probands with TTC19 pathogenic variants with Leigh syndrome spectrum have been reported in 6 publications (PMID: 25452764, 25887401, 25772319 ,29961508, 21278747, 24397319) to reach a max case-level evidence score of 12. This gene-disease association is further supported by evidence of TTC19 protein interaction with other genes associated with Leigh syndrome spectrum, TTC19 expression in brain, mitochondrial alterations in patient cell lines, and a TTC19 mouse model and fly model collectively exhibiting neuroimaging, biochemical, and neurocognitive phenotype that recapitulates symptoms of Leigh syndrome spectrum reaching a max experimental score of 6 pts. In summary, there is definitive evidence to support the relationship between TTC19 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 21, 2019 (SOP Version 7).

mitochondrial complex III deficiency nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014063

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex III deficiency nuclear type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014063

Submitter: G2P

mitochondrial complex III deficiency nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014063

Submitter: Genomics England PanelApp

mitochondrial complex III deficiency nuclear type 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014063

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mitochondrial complex III deficiency, nuclear type 2AR

Manifestation: Biochemical; Musculoskeletal; 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

Comments: Individuals may suffer acute episodes of metabolic crisis; Treatment with Mitochondrial cocktail type therapy may be beneficial

Refs: 21278747; 23532514; 24368687; 24397319

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTC19 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 181

Inborn genetic diseasesTotal: 73

Mitochondrial complex III deficiency nuclear type 2Total: 57

not specifiedTotal: 38

TTC19-related disorderTotal: 10

Mitochondrial diseaseTotal: 2

AutismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017775.4. 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			3 clinvar	49 clinvar	2 clinvar	54
missense		1 clinvar	106 clinvar	14 clinvar		121
nonsense	10 clinvar	2 clinvar	2 clinvar			14
start loss		1 clinvar				1
frameshift	5 clinvar	2 clinvar	1 clinvar	1 clinvar		9
splice donor/acceptor (+/-2bp)	1 clinvar	11 clinvar	6 clinvar			18
Total	16	17	118	64	2	217

Highest pathogenic variant AF is 0.00006282978

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017775.4	RefSeq	NP_060245.3	10	MANE Select
ENST00000261647.10	Ensembl	ENSP00000261647.5	10	MANE Select
NM_001271420.2	RefSeq	NP_001258349.1	8	Standard
ENST00000466729.5	Ensembl	ENSP00000466261.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitotic cytokinesis
mitochondrial respiratory chain complex III assembly
oxidation-reduction process

Molecular Function

protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
centrosome
midbody
respirasome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261647
Coding exons: 10
Length: 45636
Individuals with no LoFs: 125621
Homozygous LoFs: 0
Heterozygous LoFs: 127
Defined: 125748
p: 0.000505

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0827	176	179	0.983	0.00000880	2434
Missense (PolyPhen)		51	56.365	0.90482		761
Synonymous	-1.21	79	66.4	1.19	0.00000331	745
Loss of Function	1.16	15	20.7	0.725	9.77e-7	251

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00077	0.00076	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1 (PubMed:21278747, PubMed:28673544). Involved in the clearance of UQCRFS1 N-terminal fragments, which are produced upon incorporation of UQCRFS1 into the complex III and whose presence is detrimental for its catalytic activity (PubMed:28673544). {ECO:0000269|PubMed:21278747, ECO:0000269|PubMed:28673544}.;
Disease: DISEASE: Mitochondrial complex III deficiency, nuclear 2 (MC3DN2) [MIM:615157]: A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. {ECO:0000269|PubMed:21278747}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0786

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: N
Indispensability score: 0.0761

Gene Damage Prediction

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