SERAC1

protein-coding

serine active site containing 1, the group of Armadillo like helical domain containing

Gene summary

The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Aug 2012]

MANE transcript

NM_032861.4

Inheritance

ClinVar variants

P:61U:167B:97

Top phenotype

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr6:158,109,519-158,168,280

External References & Databases

Ensembl (ENSG00000122335)

Transcript & Mutation Effects

hg38 • Region Span ~58.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013875

Submitter: G2P

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013875

Submitter: PanelApp Australia

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SERAC1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The SERAC1 gene encodes serine active site-containing protein 1 which has a critical role in phosphatidylglycerol remodeling essential for both mitochondrial function and intracellular cholesterol trafficking. The SERAC1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22683713). Of note, the clinical features associated with SERAC1-related disease have been termed ‘MEGDEL’ which is an acronym for ‘3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome’, and is also sometimes referred to as MEGD(H)EL syndrome, to include hepatic dysfunction, which is a frequent manifestation in the first year of life. Evidence supporting the gene-disease relationship between SERAC1 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included six unique variants identified in six cases from four publications (PMIDs: 29205472, 23918762, 23707711, 22683713). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression data, functional alteration in patient cells, and rescue in patient cells (PMID: 22683713). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the gene-disease association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 8, 2020 (SOP Version 7).

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013875

Submitter: Labcorp Genetics (formerly Invitae)

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013875

Submitter: Orphanet

Clinical Genomic Database (CGD)

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; 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

Refs: 16527507; 22683713; 23707711

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERAC1 variants in ClinVar

9 Conditions Cataloged

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeTotal: 317

not providedTotal: 163

Inborn genetic diseasesTotal: 81

not specifiedTotal: 55

SERAC1-related disorderTotal: 43

Mitochondrial oxidative phosphorylation disorderTotal: 1

Leigh syndromeTotal: 1

Possible mitochondrial disorder - nuclear genesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032861.4. 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			4 clinvar	76 clinvar	2 clinvar	82
missense	2 clinvar	8 clinvar	153 clinvar	19 clinvar		182
nonsense	12 clinvar	9 clinvar				21
start loss						0
frameshift	10 clinvar	10 clinvar	4 clinvar			24
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	6 clinvar			16
Total	27	34	167	95	2	325

Highest pathogenic variant AF is 0.000059763115

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032861.4	RefSeq	NP_116250.3	16	MANE Select
ENST00000647468.2	Ensembl	ENSP00000496731.1	16	MANE Select
ENST00000367101.5	Ensembl	ENSP00000356068.1	15	Standard
ENST00000367101.6	Ensembl	ENSP00000356068.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

phospholipid biosynthetic process
extracellular matrix organization
intracellular cholesterol transport
phosphatidylglycerol acyl-chain remodeling

Molecular Function

molecular_function

Cellular Component

mitochondrion
endoplasmic reticulum
integral component of membrane
extracellular matrix
mitochondria-associated endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367104
Coding exons: 16
Length: 58777
Individuals with no LoFs: 125637
Homozygous LoFs: 0
Heterozygous LoFs: 111
Defined: 125748
p: 0.000441

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.49	278	357	0.778	0.0000187	4271
Missense (PolyPhen)		66	114.02	0.57885		1308
Synonymous	1.49	100	121	0.828	0.00000630	1240
Loss of Function	3.39	16	38.8	0.412	0.00000225	447

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.0017	0.0017	notable
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00042	0.00042	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. May catalyze the remodeling of phosphatidylglycerol and be involved in the transacylation- acylation reaction to produce phosphatidylglycerol-36:1. May be involved in bis(monoacylglycerol)phosphate biosynthetic pathway. {ECO:0000269|PubMed:22683713}.;

Recessive Scores

pRec: 0.0972

Intolerance Scores

LoFtool: 0.440
RVIS EVS: 0.24
RVIS percentile EVS: 69.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.168

Gene Damage Prediction

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