NM_002769.5(PRSS1):c.623G>C (p.Gly208Ala) AND Hereditary pancreatitis

Germline classification:: Conflicting classifications of pathogenicity (6 submissions)
Last evaluated:: Jan 23, 2025
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000472464.41

Allele description [Variation Report for NM_002769.5(PRSS1):c.623G>C (p.Gly208Ala)]

NM_002769.5(PRSS1):c.623G>C (p.Gly208Ala)

Genes:

TRB:T cell receptor beta locus [Gene - HGNC]
PRSS1:serine protease 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_002769.5(PRSS1):c.623G>C (p.Gly208Ala)

HGVS:

NC_000007.14:g.142752899G>C
NG_001333.2:g.586567G>C
NG_008307.3:g.8416G>C
NM_002769.5:c.623G>CMANE SELECT
NP_002760.1:p.Gly208Ala
LRG_1013t1:c.623G>C
LRG_1013:g.8416G>C
LRG_1013p1:p.Gly208Ala
NC_000007.13:g.142460750G>C
NM_002769.4:c.623G>C
p.Gly208Ala

Protein change:

G208A

Links:

dbSNP: rs189270875

NCBI 1000 Genomes Browser:

rs189270875

Molecular consequence:

NM_002769.5:c.623G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary pancreatitis (PCTT)
Synonyms:: Hereditary chronic pancreatitis
Identifiers:: MONDO: MONDO:0008185; MedGen: C0238339; Orphanet: 676; OMIM: 167800

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000562335	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 23, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000966917	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 13, 2016)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24780743, 17003641, 21415673, 24413785, 23686146, 23455445, 24033266
SCV001187149	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 14, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21415673, 23455445, 23686146, 24413785, 24780743, 27409067, 27578509, 30420730 Citation Link,
SCV001471982	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Jun 29, 2023)	germline	clinical testing	Citation Link,
SCV004099370	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Uncertain significance (Oct 30, 2023)	germline	clinical testing
SCV005916484	Department of Pathology and Laboratory Medicine, Sinai Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 6, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis.

Keiles S, Kammesheidt A.

Pancreas. 2006 Oct;33(3):221-7.

PubMed [citation]

PMID:: 17003641

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000562335.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966917.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Ambry Genetics, SCV001187149.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.G208A variant (also known as c.623G>C), located in coding exon 5 of the PRSS1 gene, results from a G to C substitution at nucleotide position 623. The glycine at codon 208 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in multiple individuals with pancreatitis, often with variants in other pancreatitis-associated genes (Hegyi E et al. JOP, 2014 Jan;15:49-52; Lee YJ et al. Gut, 2015 Feb;64:359-60; Cho SM et al. Ann Lab Med, 2016 Nov;36:555-60; Saito N et al. J Pediatr Gastroenterol Nutr, 2016 10;63:431-6). The variant was also significantly associated with idiopathic chronic pancreatitis in Japanese and Chinese cohorts (Masamune A et al. Gut, 2014 Feb;63:366; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204). In one functional study, this alteration retained normal trypsin activity; however, it also resulted in reduced trypsinogen secretion (Schnúr A et al. Gut, 2014 Feb;63:337-43), which may be consistent with an alternate mechanism of disease pathogenesis. Based on data from gnomAD, the C allele has an overall frequency of 0.07% (202/282874) total alleles studied. The highest observed frequency was 0.99% (197/19954) of East Asian alleles. This amino acid position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, disease penetrance is expected to be variable.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471982.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PRSS1 c.623G>C; p.Gly208Ala variant (rs189270875) is reported in the literature in multiple individuals affected with pancreatitis, some of whom carry additional pathogenic variants in the CFTR or SPINK1 genes (Cho 2016, Hegyi 2014, Keiles 2006, Lee 2015, Masamune 2014, Saito 2016, Xiao 2017, Zou 2018). However, this variant has also been reported in asymptomatic individuals (Hegyi 2014, Zou 2018). This variant is reported in ClinVar (Variation ID: 258802), and is found in the East Asian population with an allele frequency of 0.99% (197/19954 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.368). Functional analyses of the variant protein show normal autoactivation but a moderate reduction in secretion (Schnur 2014), which has been shown to cause ER stress and increase the risk of pancreatitis for other PRSS1 variants (Sahin-Toth 2017). While the increased prevalence in pancreatitis patients suggests that this variant may increase the risk for pancreatitis, due to conflicting information, the clinical significance of the p.Gly208Ala variant is uncertain at this time. References: Cho SM et al. PRSS1, SPINK1, CFTR, and CTRC Pathogenic Variants in Korean Patients With Idiopathic Pancreatitis. Ann Lab Med. 2016 Nov;36(6):555-60. PMID: 27578509. Hegyi E et al. Chronic pancreatitis associated with the p.G208A variant of PRSS1 gene in a European patient. JOP. 2014 Jan 10;15(1):49-52. PMID: 24413785. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Lee YJ et al. The PRSS1 c.623G>C (p.G208A) mutation is the most common PRSS1 mutation in Korean children with hereditary pancreatitis. Gut. 2015 Feb;64(2):359-60. PMID: 24780743. Masamune A et al. PRSS1 c.623G>C (p.G208A) variant is associated with pancreatitis in Japan. Gut. 2014 Feb;63(2):366. PMID: 23686146. Sahin-Toth M et al. Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. Curr Opin Gastroenterol. 2017 Sep;33(5):390-395. PMID: 28650851. Saito N et al. Genetic Analysis of Japanese Children With Acute Recurrent and Chronic Pancreatitis. J Pediatr Gastroenterol Nutr. 2016 Oct;63(4):431-6. PMID: 27409067. Schnur A et al. Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut. 2014 Feb;63(2):337-43. PMID: 23455445. Xiao Y et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. PMID: 29173301. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004099370.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System, SCV005916484.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

ClinVar

Relating variation to medicine