HACD1

protein-coding

3-hydroxyacyl-CoA dehydratase 1, the group of 3-hydroxyacyl-CoA dehydratase family

Gene summary

The protein encoded by this gene contains a characteristic catalytic motif of the protein tyrosine phosphatases (PTPs) family. The PTP motif of this protein has the highly conserved arginine residue replaced by a proline residue; thus it may represent a distinct class of PTPs. Members of the PTP family are known to be signaling molecules that regulate a variety of cellular processes. This gene was preferentially expressed in both adult and fetal heart. A much lower expression level was detected in skeletal and smooth muscle tissues, and no expression was observed in other tissues. The tissue specific expression in the developing and adult heart suggests a role in regulating cardiac development and differentiation. [provided by RefSeq, Jul 2008]

Previous symbols:

PTPLA

MANE transcript

NM_014241.4

Inheritance

AR, AD

ClinVar variants

P:14U:78B:42

Top phenotype

Congenital myopathy 11

gnomAD constraint

pLI —, LoF o/e 1.1

Max pathogenic AF

—

Genomic locus

chr10:17,589,032-17,617,374

External References & Databases

Ensembl (ENSG00000165996)

Transcript & Mutation Effects

hg38 • Region Span ~28.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019952

Submitter: ClinGen

HACD1 was first reported in relation to autosomal recessive congenital myopathy in 2013 (Muhammad et al., PMID: 23933735). This first report characterized a proband harboring a nonsense variant, with several other cases detailing a missense variant in a consanguineous family (PMID: 28781516), and a homozygous LINE insertion in Exon 6 (PMID: 32426512). Most recently, three consanguineous probands from different families were characterized each harboring a splice-altering or premature termination variant likely leading to nonsense-mediated decay (PMID: 33354762). Evidence supporting this gene-disease relationship includes six families with case-level data and a large amount of experimental data, including a naturally occuring model of myopathy in canines. Variants in this gene have been reported in six consanguineous probands and segregated with disease in nine additional family members. All variants are absent from gnomAD. The mechanism for disease is homozygous loss of function, with modified very-long-chain fatty acids causing a reduction in membrane flexibility and altering myoblast fusion in development and into adulthood specifically affecting T-tubule organization. This is similar to the pathogenic mechanisms in centronuclear myopathies caused by mutations in BIN1, DNM2, and RYR1 (PMIDs: 26160855, 27939133). While fiber-type disproportion is commonly observed in human probands, centrally nucleated muscle fibers characteristic of the centronuclear myopathies have not. This may be due to the young ages affecting the histological phenotypes or a potential compensatory effect of two HACD1 paralogues - HACD2 and HACD3 (PMID: 33354762). This gene-disease association is supported by both a canine model with a large LINE insertion that eliminates protein expression and a KO mouse model, both of which recapitulate the main muscle-related phenotypes displayed in humans. HACD1's function of moderating myoblast fusion via VLCFAs and the altered effects demonstrated on cultured cells, as well as its relatively high prevalence in skeletal muscle, also provide contributing evidence. In summary, HACD1 is definitively associated with autosomal recessive congenital myopathy. Although the rarity of reported cases previously limited the strength of genetic evidence, the strong experimental evidence and recent probands provide more than sufficent evidence to characterize this relationship.

congenital myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019952

Submitter: PanelApp Australia

congenital myopathy 11DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0859264

Submitter: G2P

congenital fiber-type disproportion myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009711

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital myopathy 11AR

Manifestation: Musculoskeletal

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: 23933735; 32426512; 33354762

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HACD1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 149

Inborn genetic diseasesTotal: 27

Congenital myopathy 11Total: 6

not specifiedTotal: 5

HACD1-related disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014241.4. 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			2 clinvar	34 clinvar	3 clinvar	39
missense			70 clinvar	4 clinvar		74
nonsense	4 clinvar	1 clinvar	1 clinvar			6
start loss			2 clinvar		1 clinvar	3
frameshift	5 clinvar					5
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	3 clinvar			7
Total	11	3	78	38	4	134

Highest pathogenic variant AF is 0.000017353472

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014241.4	RefSeq	NP_055056.3	7	MANE Select
ENST00000361271.8	Ensembl	ENSP00000355308.3	7	MANE Select
ENST00000326961.6	Ensembl	ENSP00000322923.6	2	Standard
ENST00000326961.7	Ensembl	ENSP00000322923.6	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Biosynthesis of unsaturated fatty acids - Homo sapiens (human)
Fatty acid elongation - Homo sapiens (human)
Metabolism of lipids
Fatty acyl-CoA biosynthesis
Metabolism

Biological Process

multicellular organism development
sphingolipid biosynthetic process
fatty acid elongation
long-chain fatty-acyl-CoA biosynthetic process
very long-chain fatty acid biosynthetic process

Molecular Function

3-hydroxyacyl-CoA dehydratase activity
3R-hydroxyacyl-CoA dehydratase activity
very-long-chain 3-hydroxyacyl-CoA dehydratase activity
3-hydroxy-arachidoyl-CoA dehydratase activity
3-hydroxy-behenoyl-CoA dehydratase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361271
Coding exons: 7
Length: 27419
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125742
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.511	114	130	0.874	0.00000655	1801
Missense (PolyPhen)		48	55.751	0.86096		697
Synonymous	0.831	37	44.0	0.841	0.00000225	551
Loss of Function	-0.310	13	11.8	1.10	5.00e-7	171

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.00012	rare
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00016	0.00016	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. {ECO:0000269|PubMed:18554506}.;
Disease: DISEASE: Myopathy, congenital, with fiber-type disproportion (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. {ECO:0000269|PubMed:23933735}. Note=The gene represented in this entry may be involved in disease pathogenesis. A loss-of-function mutation that segregates with the disease was found in four members of a consanguineous family and not identified in unaffected controls. The mutation affects the expression of the mRNA and the produced protein is catalytically inactive. {ECO:0000269|PubMed:23933735}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

RVIS EVS: 0.17
RVIS percentile EVS: 65.56

Essentials

Essential (gene trap): N