HCCS

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

Basic information

Region (hg38): X:11111300-11123086

Previous symbols: [ "MLS" ]

Links

ENSG00000004961 ∙ NCBI:3052 ∙ OMIM:300056 ∙ HGNC:4837 ∙ Uniprot:P53701 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• linear skin defects with multiple congenital anomalies 1 (Definitive), mode of inheritance: XLD
• linear skin defects with multiple congenital anomalies (Supportive), mode of inheritance: XL
• linear skin defects with multiple congenital anomalies 1 (Definitive), mode of inheritance: XL
• linear skin defects with multiple congenital anomalies 1 (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Linear skin defects with multiple congenital anomalies 1 (MIDAS syndrome)	XL	Audiologic/Otolaryngologic; Cardiovascular	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	Audiologic/Otolaryngologic; Cardiovascular; Dermatologic; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic	16059943; 17033964; 17893649; 20301767; 21200317

ClinVar

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

• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HCCS 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				10	5	15
missense	1	1	15	3	4	24
nonsense						0
start loss		1				1
frameshift						0
inframe indel		1				1
splice donor/acceptor (+/-2bp)						0
splice region			2	1		3
non coding				7	3	10
Total	1	3	15	20	12

Variants in HCCS

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

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

Position	Type	Phenotype	Significance	ClinVar
X-11112062-T-C		Linear skin defects with multiple congenital anomalies 1	Likely pathogenic (Mar 25, 2024)
X-11112064-G-A			Benign (Dec 11, 2023)
X-11112065-G-A		not specified • Intellectual disability • Inborn genetic diseases • HCCS-related disorder	Conflicting classifications of pathogenicity (Dec 02, 2023)
X-11112078-T-C			Likely benign (Dec 21, 2023)
X-11112081-T-C			Likely benign (Nov 22, 2022)
X-11112106-A-G		Inborn genetic diseases	Likely benign (Oct 03, 2022)
X-11112125-C-T			Uncertain significance (Apr 03, 2023)
X-11112154-A-T		not specified	Likely benign (Nov 03, 2015)
X-11112155-T-C			Uncertain significance (Mar 06, 2015)
X-11114527-C-T			Likely benign (Feb 05, 2019)
X-11114824-G-C			Likely benign (Nov 01, 2022)
X-11114895-C-T			Uncertain significance (Jun 27, 2017)
X-11114902-C-A		Inborn genetic diseases	Uncertain significance (Jul 08, 2021)
X-11114909-C-A			Uncertain significance (Jan 16, 2024)
X-11114909-C-T			Benign (Oct 27, 2023)
X-11114911-C-T			Benign (Sep 29, 2023)
X-11114912-G-A		Inborn genetic diseases	Uncertain significance (Jan 23, 2023)
X-11114916-A-G			Uncertain significance (Jun 25, 2023)
X-11114923-C-T		HCCS-related disorder	Benign (Dec 21, 2023)
X-11114929-G-A		HCCS-related disorder	Likely benign (Apr 20, 2020)
X-11114933-C-A		Linear skin defects with multiple congenital anomalies 1	Uncertain significance (May 03, 2020)
X-11114949-C-T		not specified • Inborn genetic diseases	Benign/Likely benign (Jan 29, 2024)
X-11114950-G-C		not specified • History of neurodevelopmental disorder	Benign/Likely benign (Dec 22, 2023)
X-11114970-T-C			Uncertain significance (Sep 01, 2021)
X-11114991-T-G		not specified	Uncertain significance (Dec 13, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HCCS	protein_coding	protein_coding	ENST00000321143	6	11778

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.886	0.114	125642	0	1	125643	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.20	75	110	0.680	0.00000875	1751
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000626	0.0000464
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Porphyrin and chlorophyll metabolism - Homo sapiens (human);Porphyrin metabolism (Consensus)

Recessive Scores

• pRec: 0.194

Intolerance Scores

• rvis_EVS: 0.33
• rvis_percentile_EVS: 73.11

Haploinsufficiency Scores

• pHI: 0.114
• hipred: Y
• hipred_score: 0.654
• ghis: 0.462

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.944

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hccs
• Phenotype: 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); embryo phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype

Gene ontology

• Biological process: animal organ morphogenesis;cytochrome c-heme linkage;oxidation-reduction process
• Cellular component: mitochondrion;mitochondrial inner membrane
• Molecular function: holocytochrome-c synthase activity;metal ion binding