Mendeliome
Gene: CEL Green List (high evidence)Green List (high evidence)
Comment on mode of pathogenicity: Dominant Negative Gain-of-Function experimentally establishedCreated: 6 Jan 2026, 10:53 a.m. | Last Modified: 6 Jan 2026, 10:53 a.m.
Panel Version: 1.3967
Comment on list classification: Remains technically challenging but most of critical region (First 5 repeats of exon 11 VNTR) are callable on short read data.Created: 6 Jan 2026, 10:51 a.m. | Last Modified: 6 Jan 2026, 10:51 a.m.
Panel Version: 1.3965
Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332).
Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene (pLI = 0, o/e = 0.74), further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance.
Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign.
From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.Created: 6 Jan 2026, 10:22 a.m. | Last Modified: 6 Jan 2026, 10:29 a.m.
Panel Version: 0.92
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Maturity-onset diabetes of the young, type VIII, MIM#609812
Publications
Mode of pathogenicity
Other
Green List (high evidence)
All cases of monogenic diabetes convincingly attributed to this gene have been single base deletions in the proximal VNTR repeats that alter and shorten the VNTR repeat region and lead to the rare syndrome of autosomal dominant diabetes with exocrine pancreatic dysfunction with measurable fecal elastase deficiency or hereditary pancreatitis.
MODERATE rating ClinGen MODY expert panelCreated: 13 Nov 2023, 11:08 a.m. | Last Modified: 13 Nov 2023, 11:08 a.m.
Panel Version: 1.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
I don't know
Only frameshift mutations in the VNTR-containing exon 11 have evidence for pathogenicity.Created: 27 Feb 2020, 12:55 p.m. | Last Modified: 27 Feb 2020, 12:55 p.m.
Panel Version: 0.1446
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Maturity-onset diabetes of the young, type VIII
Publications
Red List (low evidence)
Current studies show only VNTR convincingly cause this condition, not SNVs
Single study (PMID;27650499) shows some protein consequence from SNVs, but their presence in patients is questionableCreated: 25 Feb 2020, 8:49 a.m. | Last Modified: 25 Feb 2020, 8:49 a.m.
Panel Version: 0.3
Phenotypes
Maturity-onset diabetes of the young, type VIII
Publications
Mode of pathogenicity for gene: CEL was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag technically challenging tag was added to gene: CEL.
Mode of pathogenicity for gene: CEL was changed from to Other
Publications for gene: CEL were set to 24062244; 21784842; 19760265; 18544793; 17989309; 16369531; 29233499; 27650499
Gene: cel has been classified as Green List (High Evidence).
Gene: cel has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CEL were changed from to Maturity-onset diabetes of the young, type VIII
Publications for gene: CEL were set to
Mode of inheritance for gene: CEL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: cel has been classified as Amber List (Moderate Evidence).
gene: CEL was added gene: CEL was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: CEL was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.