Submissions for variant NM_002769.5(PRSS1):c.674A>G (p.Lys225Arg)

gnomAD frequency: 0.00006  dbSNP: rs541223359

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594431	SCV000703393	uncertain significance	not provided	2016-11-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814171	SCV000954572	uncertain significance	Hereditary pancreatitis	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 225 of the PRSS1 protein (p.Lys225Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PRSS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498401). 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 not expected to disrupt PRSS1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000814171	SCV001187832	likely benign	Hereditary pancreatitis	2019-03-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192439	SCV001360557	likely benign	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: PRSS1 c.674A>G (p.Lys225Arg) results in a conservative amino acid change in a region without high sequence homology to the pseudogenes. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251416 control chromosomes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRSS1 causing Chronic Pancreatitis Risk phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.674A>G in individuals affected with Chronic Pancreatitis Risk and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. However, one database (Global Variome shared LOVD) lists this variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000814171	SCV002534768	likely benign	Hereditary pancreatitis	2021-05-20	criteria provided, single submitter	curation
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000594431	SCV001798262	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000594431	SCV001974747	likely benign	not provided		no assertion criteria provided	clinical testing