rs111033565

chr7-142751938-G-Achr7-142751938-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM5 PP5_Very_Strong

The NM_002769.5(PRSS1):c.365G>A(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 0.140

Genes affected

PRSS1 (HGNC:9475): (serine protease 1) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved to its active form in the small intestine. It is active on peptide linkages involving the carboxyl group of lysine or arginine. Mutations in this gene are associated with hereditary pancreatitis. This gene and several other trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_002769.5 (PRSS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 11882
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_002769.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-142751937-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-142751938-G-A is Pathogenic according to our data. Variant chr7-142751938-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142751938-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-142751938-G-A is described in Lovd as [Pathogenic]. Variant chr7-142751938-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.365G>A	p.Arg122His	missense_variant	3/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.365G>A	p.Arg122His	missense_variant	3/5	1	NM_002769.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8 AN: 145178 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.000157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000302

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251304 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000147 AC: 21 AN: 1428358 Hom.: 0 Cov.: 62 AF XY: 0.0000140 AC XY: 10 AN XY: 711842

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000551 AC: 8 AN: 145292 Hom.: 0 Cov.: 31 AF XY: 0.0000423 AC XY: 3 AN XY: 70924

Gnomad4 AFR AF: 0.000156

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000302

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Pathogenic:12 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	The PRSS1 c.365G>A; p.Arg122His variant (rs111033565) is reported in the literature as the most common pathogenic variant associated with hereditary pancreatitis (Nemeth and Sahin-Toth 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11876). This variant increases the auto-activation and stability of trypsin, even in the presence of inhibitory factors such as chymotrypsin C (Sahin-Toth 2000, Szabo 2012, Whitcomb 1996), and leads to chronic pancreatic inflammation and acinar cell necrosis in a mouse model (Archer 2006). Based on available information, this variant is considered pathogenic for the development of pancreatitis. References: Archer H et al. A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology. 2006; 131(6):1844-55. PMID: 17087933. Nemeth BC and Sahin-Toth M. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2014 Mar;306(6):G466-73. PMID: 24458023. Sahin-Toth M et al. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun. 2000; 278(2):286-9. PMID: 11097832. Szabo A et al. Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. J Biol Chem. 2012; 287(24):20701-10. PMID: 22539344. Whitcomb D et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996; 14(2):141-5. PMID: 8841182. -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2019	Variant summary: PRSS1 c.365G>A (p.Arg122His) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246622 control chromosomes (gnomAD). c.365G>A has been reported in the literature in multiple individuals affected with Chronic Pancreatitis (Sofia_2016, Dasouki_1998, Whitcomb_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to increase autolytic stability of trypsin and enhance autocatalytic trypsin generation (Sahin-Toth_2000), resulting in a gain of function effect. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 2021	The p.R122H pathogenic mutation (also known as c.365G>A), located in coding exon 3 of the PRSS1 gene, results from a G to A substitution at nucleotide position 365. The arginine at codon 122 is replaced by histidine, an amino acid with highly similar properties. This mutation is one of the most common mutations observed in families with hereditary pancreatitis. In one study, this mutation was detected in 105/135 (78%) PRSS1 mutation carriers from 50 unrelated families (Rebours V et al. Gut, 2009 Jan;58:97-103). In addition, an in vitro study demonstrated that this mutation results in a markedly higher active trypsin level compared to wild type and is resistant to degradation (Szabó A et al. J. Biol. Chem., 2012 Jun;287:20701-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The PRSS1 (c.365G>A) variant has been reported in heterozygous state in individuals affected with Pancreatitis, hereditary (Sahin-Tóth et. al., 2000), and is the most frequent mutation found in individuals with the same disorder (Chen et. al., 2009). Experimental studies have shown that this missense change leads to an increase in both PRSS1 stability and trypsinogen activity, due to an inhibition of autolysis (Kukor et. al., 2002; Sahin-Tóth et. al., 2000). A different missense substitution at this codon (p.Arg122Cys) has been determined to be pathogenic (Chen et. al., 2009), further demonstrating that the arginine residue is critical for normal inactivation of trypsinogen in the pancreas, and that other missense substitutions at this position may also be pathogenic. The p.Arg122His variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.001% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 122 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg122His in PRSS1 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 24, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11097832, 11748242, 31419436). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011876 / PMID: 8841182). A different missense change at the same codon (p.Arg122Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011883 / PMID: 11788572). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 122 of the PRSS1 protein (p.Arg122His). 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 missense change has been observed in individual(s) with HP (PMID: 8841182, 19453252). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg117His or R117H. ClinVar contains an entry for this variant (Variation ID: 11876). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRSS1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRSS1 function (PMID: 11097832, 11748242). This variant disrupts the p.Arg122 amino acid residue in PRSS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19453252). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	The R122H variant in the PRSS1 gene has been reported previously in association with hereditary pancreatitis in multiple unrelated individuals from diverse ethnic backgrounds (Whitcomb et al., 1996; Nishimori et al., 1999; Saito et al., 2016). The R122H variant is the most common pathogenic variant associated with hereditary pancreatitis (Nemeth and Sahin-Toth, 2014). The R122H variant is is not observed in large population cohorts (Lek et al., 2016). The R122H variant is a conservative amino acid substitution and occurs at a position that is not conserved. Functional studies demonstrated that the R122H variant significantly enhanced autoactivation of cationic trypsinogen in vitro and inhibited autocatalytic inactivation of trypsin (Sahin-Toth et al., 2000). Therefore, we interpret R122H as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

PRSS1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2024

The PRSS1 c.365G>A variant is predicted to result in the amino acid substitution p.Arg122His. This variant, also described as p.Arg117His in earlier publications, has been reported multiple times to be causative for chronic pancreatitis and is one of the most commonly reported causative variants (see for example Whitcomb et al. 1996. PubMed ID: 8841182; Archer et al. 2006. PubMed ID: 17087933). This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/11876/). We interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	1.5
Dann	Benign	0.65
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	9.6e-10	A;A
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.16	N;.;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.39	T;.;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.0020	B;.;B;.
Vest4		0.73
MutPred		0.63		Loss of MoRF binding (P = 0.0328);.;.;.;
MVP		0.86
MPC		0.20
ClinPred		0.028	T
GERP RS		-0.75
Varity_R		0.21
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033565; hg19: chr7-142459789; COSMIC: COSV104604888; COSMIC: COSV104604888;