EFHC1

protein-coding

EF-hand domain containing 1, the group of EF-hand domain containing

Gene summary

This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

Previous symbols:

EJM1
EJM

MANE transcript

NM_018100.4

Inheritance

ClinVar variants

P:2U:286B:101

Top phenotype

Epilepsy, myoclonic juvenile; Epilepsy, juvenile absence, susceptibility to, 1

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr6:52,362,123-52,529,886

External References & Databases

Ensembl (ENSG00000096093)

Transcript & Mutation Effects

hg38 • Region Span ~167.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*EFHC1* was first reported in relation to autosomal dominant epilepsy in 2004 with five different missense variants identified in probands from six unrelated families (Suzuki et al, PMID: 15258581). Numerous additional probands with epilepsy have been reported to have variants in *EFHC1* (PMIDs: 17634063, 22690745, 22727576, 16839746, 17159113, 15258581). However, many of these variants are observed in population databases at frequencies too high to be considered pathogenic, with minor allele frequencies (MAF) of 2.857e-5 to 0.05973. Functional studies do not provide a consistent mechanism of disease. In summary, the evidence supporting the relationship between *EFHC1* and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. This gene-disease pair was originally evaluated by the ClinGen Epilepsy Gene Curation Expert Panel on June 18, 2018. It was reevaluated on September 5, 2023. As a result of this reevaluation, the classification changed from Disputed to Refuted. Since 2018, there have been additional individuals reported with epilepsy and variants in *EFHC1*. However, these variants are found in gnomAD at high allele frequencies, or do not have convincing segregation or functional evidence to support this gene-disease relationship (PMID: 18505993, 33969125, 36842888). Additionally, a recent publication compared the frequency of ultra rare *EFHC1* variants in over 15,000 patients and approximately 11,000 controls. The authors determined that the frequency of variants in *EFHC1* did not differ between patients and controls (PMID: 31056551). This evidence, in combination with the lack of case-level evidence to support this gene-disease relationship, has led the Epilepsy GCEP to refute the relationship between autosomal dominant epilepsy and *EFHC1*.

epilepsyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: PanelApp Australia

juvenile myoclonic epilepsyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009696

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epilepsy, myoclonic juvenile; Epilepsy, juvenile absence, susceptibility to, 1AD

Manifestation: 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: As with other forms of epilepsy, optimal seizure control is advantageous, and genetic diagnosis may aid with medication selection

Refs: 7668263; 12439895; 15258581; 17159113; 18505993; 19147686; 22690745; 22727576; 22926142

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EFHC1 variants in ClinVar

10 Conditions Cataloged

Myoclonic epilepsy, juvenile, susceptibility to, 1Total: 298

Absence seizureTotal: 271

not specifiedTotal: 147

not providedTotal: 107

Typical absence seizureTotal: 25

Juvenile myoclonic epilepsyTotal: 15

EFHC1-related disorderTotal: 15

Epilepsy, juvenile absence, susceptibility to, 1Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018100.4. 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			6 clinvar	66 clinvar	2 clinvar	74
missense			241 clinvar	31 clinvar	1 clinvar	273
nonsense		1 clinvar	16 clinvar			17
start loss			1 clinvar			1
frameshift	1 clinvar		14 clinvar			15
splice donor/acceptor (+/-2bp)			8 clinvar	1 clinvar		9
Total	1	1	286	98	3	389

Highest pathogenic variant AF is 0.000051424202

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_018100.4	RefSeq	NP_060570.2	11	MANE Select
ENST00000371068.11	Ensembl	ENSP00000360107.4	11	MANE Select
NM_001172420.2	RefSeq	NP_001165891.1	11	Standard
ENST00000480623.6	Ensembl	ENSP00000434498.2	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitotic cytokinesis
mitotic spindle organization
cerebral cortex cell migration
regulation of cell division

Molecular Function

calcium ion binding
protein binding
protein C-terminus binding
alpha-tubulin binding

Cellular Component

spindle pole
centrosome
axoneme
neuronal cell body
mitotic spindle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371068
Coding exons: 11
Length: 102787
Individuals with no LoFs: 125616
Homozygous LoFs: 0
Heterozygous LoFs: 132
Defined: 125748
p: 0.000525

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.141	350	357	0.979	0.0000213	4221
Missense (PolyPhen)		93	101.88	0.91287		1192
Synonymous	0.456	122	129	0.949	0.00000738	1207
Loss of Function	0.632	28	31.8	0.879	0.00000198	367

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00046	0.00046	rare
Ashkenazi Jewish	0.00089	0.00089	rare
East Asian	0.00076	0.00076	rare
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.00052	0.00051	rare
South Asian	0.00049	0.00049	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Microtubule-associated protein which regulates cell division and neuronal migration during cortical development. Necessary for mitotic spindle organization (PubMed:19734894, PubMed:28370826). Necessary for radial and tangential cell migration during brain development, possibly acting as a regulator of cell morphology and process formation during migration (PubMed:22926142). May enhance calcium influx through CACNA1E and stimulate programmed cell death (PubMed:15258581). {ECO:0000269|PubMed:15258581, ECO:0000269|PubMed:19734894, ECO:0000269|PubMed:22926142, ECO:0000269|PubMed:28370826}.;
Disease: DISEASE: Juvenile absence epilepsy 1 (JAE1) [MIM:607631]: A subtype of idiopathic generalized epilepsy characterized by onset occurring around puberty, absence seizures, generalized tonic- clonic seizures (GTCS), GTCS on awakening, and myoclonic seizures. {ECO:0000269|PubMed:17159113, ECO:0000305|PubMed:17159113}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=Mutation Leu-229 may be a cause of intractable epilepsy of infancy. Affected individuals have seizures of multiple type, manifested as tonic, clonic, and myoclonic seizures in the neonatal period, and as tonic seizures activated frequently by sleep, and repeated frequent myoclonic seizures in later infancy. The seizures are unresponsive to numerous antiepileptic drugs, and infants die in the first years of life. Although heterozygosity for Leu-229 has been associated with relatively benign forms of epilepsy in adolescence, homozygosity for the same mutation has much more severe consequences. {ECO:0000269|PubMed:22690745}.;

Recessive Scores

pRec: 0.155

Intolerance Scores

LoFtool: 0.993
RVIS EVS: 1.27
RVIS percentile EVS: 93.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.865

Gene Damage Prediction

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