CRELD1

protein-coding

cysteine rich with EGF like domains 1

Gene summary

This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

Previous symbols:

AVSD2

MANE transcript

NM_001077415.3

Inheritance

AR, AD

ClinVar variants

P:23U:116B:42

Top phenotype

Atrioventricular septal defect, partial, with or without heterotaxy; Jeffries-Lakhani neurodevelopmental syndrome

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr3:9,933,793-9,945,413

External References & Databases

Ensembl (ENSG00000163703)

Transcript & Mutation Effects

hg38 • Region Span ~11.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

Jeffries-Lakhani neurodevelopmental syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0958329

Submitter: G2P

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*CRELD1* was first reported in relation to autosomal dominant Congenital heart disease in 2003 (Robinson et al., PMID: 12632326). *CRELD1* has been noted to be associated with the following disease entities: Atrioventricular septal defect (AVSD), susceptibility to 2; AVSD, partial, with heterotaxy syndrome; AVSD, Down syndrome-associated; congenital heart defect (CHD); tetralogy of Fallot (TOF); left ventricular noncompaction (LVNC); and Jeffries-Lakhani neurodevelopmental syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability of AVSD, AVSD with heterotaxy syndrome, CHD, and TOF. Therefore, these disease entities have been lumped into one disease entity. The split curation for Jeffries-Lakhani neurodevelopmental syndrome and AVSD, Down syndrome- associated will be curated separately. A missense variant that has been reported in a proband is included in this curation (PMID: 22740159). At least 21 other unique variants (missense, frameshift, splice site) have been reported in 46 probands in 11 publications (PMIDs: 12632326, 15857420, 18076106, 24927998, 22740159, 29054759, 34328347, 21413875, 21080147, 28798025, 36011280). However, these variants were not included in the curation due to either a high minor allele frequency (> 0.00001) in gnomAD v.2.1.1 or a low REVEL score (< 0.7). *CRELD1* variants are incompletely penetrant and require interactions with other risk factors to increase the risk of developing a heart defect. This gene-disease association is also supported by three knockout mouse models that show that *Creld1* is important for VEGF signaling and heart development (PMIDs: 25328912, 24697899, 33773999). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/5/2023 (SOP Version 9).

atrioventricular septal defect, susceptibility to, 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011650

Submitter: Labcorp Genetics (formerly Invitae)

atrioventricular septal defect, susceptibility to, 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011650

Submitter: G2P

Clinical Genomic Database (CGD)

Atrioventricular septal defect, partial, with or without heterotaxy; Jeffries-Lakhani neurodevelopmental syndromeAD/AR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Cardiovascular

Rationale: Atrioventricular septal defect, partial, with or without heterotaxy can involve congenital cardiac anomalies, and awareness may allow early management; Jeffries-Lakhani neurodevelopmental syndrome can involve recurrent infections and cardiovascular anomalies, including cardiac arrhythmias requiring defribillator placement, as well as cardiac malformations in some individuals, and awareness can allow early and aggressive treatment of infections as well as identification and management of cardiovascular manifestations

Refs: 12632326; 15857420; 21080147; 22740159; 3794718

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRELD1 variants in ClinVar

11 Conditions Cataloged

Atrioventricular septal defect, susceptibility to, 2Total: 110

not providedTotal: 86

Inborn genetic diseasesTotal: 55

CRELD1-related disorderTotal: 30

not specifiedTotal: 29

Jeffries-Lakhani neurodevelopmental syndromeTotal: 11

Congenital heart defects, multiple types, 4Total: 2

Ventricular septal defect 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001077415.3. 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	28 clinvar	4 clinvar	36
missense	3 clinvar	5 clinvar	102 clinvar	8 clinvar	1 clinvar	119
nonsense	2 clinvar	1 clinvar	2 clinvar			5
start loss						0
frameshift	3 clinvar	7 clinvar	3 clinvar			13
splice donor/acceptor (+/-2bp)		2 clinvar	5 clinvar	1 clinvar		8
Total	8	15	116	37	5	181

Highest pathogenic variant AF is 0.00042320267

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 156 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001077415.3	RefSeq	NP_001070883.2	10	MANE Select
ENST00000452070.6	Ensembl	ENSP00000393643.2	10	MANE Select
NM_001031717.4	RefSeq	NP_001026887.2	11	Standard
NM_001374316.1	RefSeq	NP_001361245.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

endocardial cushion development
cardiac septum development

Molecular Function

extracellular matrix structural constituent
calcium ion binding

Cellular Component

integral component of membrane
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326434
Coding exons: 11
Length: 11592
Individuals with no LoFs: 125590
Homozygous LoFs: 0
Heterozygous LoFs: 158
Defined: 125748
p: 0.000628

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.175	235	243	0.968	0.0000143	2740
Missense (PolyPhen)		84	92.424	0.90885		1018
Synonymous	-1.48	111	92.8	1.20	0.00000573	798
Loss of Function	1.36	21	28.9	0.727	0.00000182	298

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00070	0.00069	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0010	0.00099	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Atrioventricular septal defect 2 (AVSD2) [MIM:606217]: A congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum; the valve itself is also shared. A less severe form, known as ostium primum atrial septal defect, is characterized by separate atrioventricular valvar orifices despite a common junction. {ECO:0000269|PubMed:12632326, ECO:0000269|PubMed:15857420}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0922

Intolerance Scores

LoFtool: 0.424
RVIS EVS: 0.38
RVIS percentile EVS: 75.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.402

Gene Damage Prediction

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