Submissions for variant NM_001807.6(CEL):c.1776del (p.Val593fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029467	SCV000052117	likely pathogenic	Maturity-onset diabetes of the young type 8	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000029467	SCV001422784	likely pathogenic	Maturity-onset diabetes of the young type 8	2020-01-22	criteria provided, single submitter	curation	The p.Val596Cysfs variant in CEL has been reported in 4 individuals with Maturity-Onset Diabetes of the Young, segregated with disease in four affected relatives from one family (PMID: 16369531). This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 35815). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 596 and leads to a premature termination codon 111 amino acids downstream. This termination codon occurs within the the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the CEL gene is an established disease mechanism in MODY type 8. The p.Val596Cysfs is located in a region of CEL that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 16369531). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1, PM1, PVS1_moderate (Richards 2015).
OMIM	RCV000029467	SCV000039455	pathogenic	Maturity-onset diabetes of the young type 8	2006-01-01	no assertion criteria provided	literature only

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