Submissions for variant NM_001868.4(CPA1):c.829G>A (p.Gly277Ser)

gnomAD frequency: 0.00001  dbSNP: rs782790983

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002445197	SCV001189921	likely pathogenic	Hereditary pancreatitis	2024-03-19	criteria provided, single submitter	clinical testing	The p.G277S variant (also known as c.829G>A), located in coding exon 8 of the CPA1 gene, results from a G to A substitution at nucleotide position 829. The glycine at codon 277 is replaced by serine, an amino acid with similar properties. This variant was reported in one individual with chronic pancreatitis; CPA1 activity and secretion was undetectable in HEK293T cells (Witt H et al. Nat. Genet. 2013Oct;45(10):1216-20). Based on internal structural analysis, G277S is structurally destabilizing to CPA1 (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229837	SCV001402294	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 277 of the CPA1 protein (p.Gly277Ser). This variant is present in population databases (rs782790983, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with non-alcoholic chronic pancreatitis (PMID: 23955596). ClinVar contains an entry for this variant (Variation ID: 827562). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CPA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CPA1 function (PMID: 23955596). 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.
PreventionGenetics, part of Exact Sciences	RCV004758136	SCV005355732	uncertain significance	CPA1-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The CPA1 c.829G>A variant is predicted to result in the amino acid substitution p.Gly277Ser. This variant was reported in an individual with chronic pancreatitis and resulted in no detectable enzymatic activity in an in vitro functional assay (Witt et al. 2013. PubMed ID: 23955596). This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.