rs202003805

Positions:

• chr7-142750561-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BP4

The NM_002769.5(PRSS1):​c.47C>T​(p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A16A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (0 hom., cov: 36)
  • Exomes 𝑓: 0.20 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2 O:1
• Conservation: PhyloP100: 0.485

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a propeptide Activation peptide (size 7) in uniprot entity TRY1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_002769.5
• PP5: Variant 7-142750561-C-T is Pathogenic according to our data. Variant chr7-142750561-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142750561-C-T is described in UniProt as null. Variant chr7-142750561-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-142750561-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054525733). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.47C>T	p.Ala16Val	missense_variant	2/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.47C>T	p.Ala16Val	missense_variant	2/5	1	NM_002769.5	P1
PRSS1	ENST00000486171.5	c.47C>T	p.Ala16Val	missense_variant	2/6	5
PRSS1	ENST00000497041.1	n.51C>T		non_coding_transcript_exon_variant	2/2	2
PRSS1	ENST00000485223.1	n.54-68C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 45782 AN: 118562 Hom.: 0 Cov.: 36 FAILED QC

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.324

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.385

GnomAD3 exomes AF: 0.0000901 AC: 22 AN: 244118 Hom.: 0 AF XY: 0.0000679 AC XY: 9 AN XY: 132610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.202 AC: 162367 AN: 803306 Hom.: 0 Cov.: 90 AF XY: 0.205 AC XY: 82190 AN XY: 401142

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.386 AC: 45818 AN: 118638 Hom.: 0 Cov.: 36 AF XY: 0.381 AC XY: 22029 AN XY: 57794

Gnomad4 AFR AF: 0.458

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.380

Alfa AF: 0.115 Hom.: 0

ExAC AF: 0.0173 AC: 2099

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Pathogenic:8 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense PRSS1 c.47C>T (p.Ala16Val) variant in PRSS1 gene has been reported in heterozygous state in individuals affected with Pancreatitis, hereditary (Chen JM et al, 2012). Experimental studies have shown that this missense change affects PRSS1 function (Szabó A et al., 2012). The p.Ala16Val variant has allele frequency of 0.009% in the gnomAD exomes database. This variant has been submitted to the ClinVar database Uncertain Significance / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Ala16Val in PRSS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 16 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The variant PRSS1:c.47C>T (p.Ala16Val) was identified in dbSNP (ID: rs202003805) and Clinvar (classified as pathogenic). The PRSS1 p.Ala16Val variant is the third most common PRSS1 mutation and is significantly associated with pancreatitis. The variant was identified in 22 individuals across 10 different families, with 15 individuals across 6 families reporting symptoms of pancreatitis. Of these, two individuals confirmed as being PRSS1 p.Ala16Val carriers had pancreatic cancer (Grocock_2009_ PMID:19951905). In another study, the variant was detected in 4 out of 44 patients. Three of these patients had no family history of chronic pancreatitis, although the mutation was inherited in all cases by one parent. Only 1 of 7 first-degree relatives with p.Ala16Val was affected, indicating a low penetrance of this mutation (Witt_2001_PMID:12120220). The variant was identified in control databases in 22 of 244,118 chromosomes (0 homozygous) at a frequency of 0.009%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 1800 of 110,396 chromosomes (freq: 0.0163%) (Genome Aggregation Database March 6, 2019, v2.1.1. The p.Ala16Val residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 16 of the PRSS1 protein (p.Ala16Val). 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 pancreatic cancer (PMID: 10381903, 11260229, 15017610, 19453252, 19951905, 20502448, 21907651, 22749696). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38363). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PRSS1 function (PMID: 16505482, 22539344). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 03, 2021	The p.A16V pathogenic mutation (also known as c.47C>T), located in coding exon 2 of the PRSS1 gene, results from a C to T substitution at nucleotide position 47. The alanine at codon 16 is replaced by valine, an amino acid with similar properties. In pediatric individuals, heterozygosity for this mutation was associated with chronic pancreatitis (Witt H et al. Gastroenterology, 1999 Jul;117:7-10). Subsequent studies also observed this mutation in affected individuals of all ages, but suggested a reduced penetrance given the presence of asymptomatic family members (Grocock CJ et al. Gut, 2010 Mar;59:357-63; Joergensen MT et al. Am. J. Gastroenterol., 2010 Aug;105:1876-83). In addition, two functional studies demonstrated increased trypsinogen activation in vitro due to a 4- and 5.8-fold increased rate of chymotrypsin C-mediated N-terminal processing relative to wild type, respectively (Nemoda Z et al. J. Biol. Chem., 2006 Apr;281:11879-86; 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2023	Variant summary: RSS1 c.47C>T (p.Ala16Val) results in a non-conservative amino acid change in the encoded protein sequence. Ala16 is the first residue of the trypsinogen activation peptide, as the secretory signal peptide (amino acids 1-15) is cleaved off during endoplasmic reticulum entry. The activation peptide is also released during the activation process, thus A16V is not present in the active trypsin and cannot alter trypsin function, however it might affect the processing of trypsinogen by CTRC (chymotrypsin C) (Szabo_2012). 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 9e-05 in 244118 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00016 in the gnomAD database exomes dataset (of note, although the variant is located within a region of segmental duplication and therefore these values can be affected by pseudogene interference, the gnomAD database exomes dataset indicates no variant quality control issues). This frequency is not higher than the estimated expected maximum for a pathogenic variant in PRSS1 causing Chronic Pancreatitis (0.00025), allowing no conclusion about variant significance. Per published data, this variant is the third most commonly inherited mutation in the PRSS1 gene (Moran_2016) and has been reported in numerous affected individuals in dominant or compound recessive inheritance with a reported penetrance of ~50% (Grocock_2010, Rosendahl_2012). However, none of the reports confirmed that the presence of pseudogene had been ruled out. Co-occurrences with other variants have been reported (SPINK1 c.101A>G (p.Asn34Ser), in Rosendahl_2012 and Moran_2016; CFTR TG11-5T in Moran_2016; PRSS1 c.364C>T (p.Arg122Cys) in Giefer_2017) that are known as causal variants linked to pancreatitis. Trans-heterozygosity for this variant with other pathogenic variants in SPINK1 and CFTR genes and especially in the context of risk factors such as smoking could increase the risk for pancreatitis (Moran_2016). In functional studies, A16V had no effect on trypsinogen secretion and autoactivation in the absence of chymotrypsin C (Kereszturi_2009). In presence of chymotrypsin C, A16V increased the rate of autoactivation compared with wild-type cationic trypsinogen by increasing N-terminal processing, (Nemoda_2006, Nemeth_2017), albeit the magnitude of this increase was much smaller than in the case of the highly penetrant, common PRSS1 pathogenic variants (e.g. R122H, V39A; Szabo 2012). The following publications have been ascertained in the context of this evaluation (PMID: 17204147, 19191323, 22427236, 22539344, 22749696, 11260229, 24458023, 19951905, 16505482, 26658045, 25546417, 23143602, 28502372, 29173301, 29215622, 30850667, 30113427, 28536777, 15017610, 30018304, 34065437, 10381903). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=7) and VUS (n=1). In summary, although co-occurrences with known pancreatitis causative variants and a possibility the variant being derived from a pseudogene (in at least some of the reported cases) provide somewhat contradicting evidence for pathogenicity, however the lower penetrance for the variant is in accordance with a milder biochemical phenotype in functional studies, therefore the variant has been classified as likely pathogenic -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2023	The PRSS1 c.47C>T; p.Ala16Val variant (rs202003805) is one of the most common pathogenic PRSS1 variants (Rebours 2012), has been reported to co-segregate with disease in families with hereditary pancreatitis (Grocock 2010, Joergensen 2010, Rebours 2012), and is reported in the literature in individuals affected with idiopathic chronic pancreatitis (Grocock 2010, Howes 2004, Witt 1999). This variant is reported in ClinVar (Variation ID: 38363), and is found in the general population with an overall allele frequency of 0.65% (1680/256738 alleles) in the Genome Aggregation Database, but is considered a low confidence variant in the database. This variant has been described to have variable penetrance (Grocock 2010, Joergensen 2010), and in vitro assays have shown p.Ala16Val to increase cationic trypsinogen activity (Nemoda 2006, Szabo 2012). Based on functional assays and this variant's strong association with pancreatitis, the p.Ala16Val variant is considered to be pathogenic. References: Grocock CJ et al. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. 2010 Gut. 59(3):357-63. PMID: 19951905. Howes N et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004 2(3):252-61. PMID: 15017610. Joergensen MT et al. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. Am J Gastroenterol. 2010 105(8):1876-83. PMID: 20502448. Nemoda Z et al. Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen. J Biol Chem. 2006 281(17):11879-86. PMID: 16505482. Rebours V et al. An overview of hereditary pancreatitis. Dig Liver Dis. 2012 44(1):8-15. PMID: 21907651. 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. Witt H et al. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology. 1999 117(1):7-10. PMID: 10381903. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	One of the most common PRSS1 pathogenic variants observed in families with pancreatitis and suggested to have a reduced penetrance compared to other pathogenic PRSS1 variants given unaffected carriers in some families (Witt 1999, Howes 2004, Grocock 2010, Joergensen 2010, Chen 2012); Published functional studies demonstrate a damaging effect: increased rate of chymotrypsin C (CTRC)-mediated trypsinogen activation (Nemoda 2006); Case control studies suggest this variant is associated with pancreatitis (Rosendahl 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17204147, 24002981, 15082592, 19453252, 19191323, 22539344, 23143602, 27535533, 19951905, 10381903, 26658045, 25546417, 22749696, 15017610, 11788572, 16791840, 16542853, 24458023, 21907651, 11260229, 22427236, 20502448, 32547704, 32268488, 27555793, 34065437, 33504001, 34036232, 16505482) -

Recurrent pancreatitis Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	2.8
DANN	Benign	0.31
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.010	N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.57	T;.;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.072
MPC		0.16
ClinPred		0.026	T
GERP RS		0.99
Varity_R		0.017
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs202003805; hg19: chr7-142458412; COSMIC: COSV61191325; COSMIC: COSV61191325;