HCCS

protein-coding

holocytochrome c synthase, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

The protein encoded by this gene is an enzyme that covalently links a heme group to the apoprotein of cytochrome c. Defects in this gene are a cause of microphthalmia syndromic type 7 (MCOPS7). Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jan 2010]

Previous symbols:

MANE transcript

NM_005333.5

Inheritance

ClinVar variants

P:13U:69B:42

Top phenotype

Linear skin defects with multiple congenital anomalies 1 (MIDAS syndrome)

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chrX:11,111,301-11,123,086

External References & Databases

Ensembl (ENSG00000004961)

Transcript & Mutation Effects

hg38 • Region Span ~11.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

linear skin defects with multiple congenital anomalies 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024552

Submitter: Labcorp Genetics (formerly Invitae)

linear skin defects with multiple congenital anomalies 1MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0024552

Submitter: G2P

linear skin defects with multiple congenital anomalies 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024552

Submitter: PanelApp Australia

linear skin defects with multiple congenital anomaliesSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010672

Submitter: Orphanet

Clinical Genomic Database (CGD)

Linear skin defects with multiple congenital anomalies 1 (MIDAS syndrome)XL

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Dermatologic; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; As individuals have been described with a variety of cardiovascular anomalies, surveillance (eg, with echocardiogram/electrocardiogram) may allow detection and early management of related manifestations

Refs: 16059943; 17033964; 17893649; 20301767; 21200317

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HCCS variants in ClinVar

8 Conditions Cataloged

not providedTotal: 59

Inborn genetic diseasesTotal: 22

Linear skin defects with multiple congenital anomalies 1Total: 20

not specifiedTotal: 19

HCCS-related disorderTotal: 9

HCCS-related disordersTotal: 3

History of neurodevelopmental disorderTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005333.5. 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			5 clinvar	18 clinvar	6 clinvar	29
missense	1 clinvar	2 clinvar	50 clinvar	16 clinvar	2 clinvar	71
nonsense	1 clinvar	3 clinvar	5 clinvar			9
start loss	1 clinvar	1 clinvar				2
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	7 clinvar			9
Total	4	9	69	34	8	124

Highest pathogenic variant AF is 9.20545e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005333.5	RefSeq	NP_005324.3	6	MANE Select
ENST00000380762.5	Ensembl	ENSP00000370139.4	6	MANE Select
NM_001122608.3	RefSeq	NP_001116080.1	6	Standard
NM_001171991.3	RefSeq	NP_001165462.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Porphyrin and chlorophyll metabolism - Homo sapiens (human)
Porphyrin metabolism

Biological Process

animal organ morphogenesis
cytochrome c-heme linkage
oxidation-reduction process

Molecular Function

holocytochrome-c synthase activity
metal ion binding

Cellular Component

mitochondrion
mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000321143
Coding exons: 6
Length: 11778
Individuals with no LoFs: 125642
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125643
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	75	110	0.680	0.00000875	1751
Missense (PolyPhen)		14	44.892	0.31186		727
Synonymous	0.533	37	41.4	0.895	0.00000357	488
Loss of Function	2.86	1	11.5	0.0873	8.94e-7	185

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000063	0.000046	rare
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Links covalently the heme group to the apoprotein of cytochrome c. {ECO:0000250}.;
Disease: DISEASE: Linear skin defects with multiple congenital anomalies 1 (LSDMCA1) [MIM:309801]: A disorder characterized by dermal, ocular, neurological and cardiac abnormalities. LSDMCA1 main features are unilateral or bilateral microphthalmia, linear skin defects in affected females, and in utero lethality for males. Skin defects are limited to the face and neck, consisting of areas of aplastic skin that heal with age to form hyperpigmented areas. Additional features in female patients include agenesis of the corpus callosum, sclerocornea, chorioretinal abnormalities, infantile seizures, congenital heart defect, mental retardation, and diaphragmatic hernia. Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. {ECO:0000269|PubMed:17033964}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.194

Intolerance Scores

RVIS EVS: 0.33
RVIS percentile EVS: 73.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.944

Gene Damage Prediction

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