Submissions for variant NM_000209.4(PDX1):c.217dup (p.Leu73fs)

dbSNP: rs1445970498

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711999	SCV000842412	pathogenic	not provided	2017-12-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240502	SCV002556024	pathogenic	Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: PDX1 c.217dupC (p.Leu73ProfsX152) replaces the last 211 amino acids of the protein with 152 others and results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 142046 control chromosomes (gnomAD). c.217dupC has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young (e.g. Wu_2023, Saint-Martin_2022). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34556497, 37093977). ClinVar contains an entry for this variant (Variation ID: 586034). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711999	SCV005707003	uncertain significance	not provided	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu73Profs*152) in the PDX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 211 amino acid(s) of the PDX1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PDX1-related condition (PMID: 34556497, 34789499). ClinVar contains an entry for this variant (Variation ID: 586034). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.