7-142751919-C-T

Position:

chr7-142751919-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_002769.5(PRSS1):c.346C>T(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.362

Variant links:

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]

PRSS1 links:

TRB (HGNC:12155):

TRB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002769.5

PP5

Variant 7-142751919-C-T is Pathogenic according to our data. Variant chr7-142751919-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142751919-C-T is described in UniProt as null. Variant chr7-142751919-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-142751919-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5 link	c.346C>T	p.Arg116Cys	missense_variant	3/5	ENST00000311737.12	NP_002760.1	P07477

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12 link	c.346C>T	p.Arg116Cys	missense_variant	3/5	1	NM_002769.5	ENSP00000308720.7		P07477

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251478

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 20, 2024	The PRSS1 c.346C>T; p.Arg116Cys variant (rs387906698), is reported in the literature in multiple individuals and families affected with pancreatitis (Kereszturi 2009, Kurian 2014, see link to Chronic Pancreatitis database and references therein). This variant is also reported in ClinVar (Variation ID: 29923). It is observed in the East Asian population with an allele frequency of 0.07% (14/19950 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.597). However, functional analyses of the variant protein show misfolding and intracellular retention, leading to endoplasmic reticular stress (Kereszturi 2009). Based on available information, the p.Arg116Cys variant is considered to be pathogenic. References: Link to Genetic Risk Factors in Chronic Pancreatitis database: http://pancreasgenetics.org/e107_plugins/aacgc_itemlist/Item_List.php?det.1 Kereszturi E et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009 Apr;30(4):575-82. PMID: 19191323. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9. PMID: 24733792. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2024	Variant summary: PRSS1 c.346C>T (p.Arg116Cys) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-05 in 255866 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRSS1 causing Chronic Pancreatitis (7e-05 vs 0.00025), allowing no conclusion about variant significance. c.346C>T has been reported in the literature in multiple individuals affected with Pancreatitis (examples, Teich_2002, Tautermann_2001, LeMarechalPRSS1_2001, Rosendahl_2012, Kereszturi_2009, Sultan_2012, Pho-Iam_2005). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Kereszturi_2009). The following publications have been ascertained in the context of this evaluation (PMID: 20452997, 19191323, 11842279, 15786540, 16791840, 22094894, 22427236, 11708864, 11866271). ClinVar contains an entry for this variant (Variation ID: 29923). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 116 of the PRSS1 protein (p.Arg116Cys). 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 pancreatitis (PMID: 11708864, 11842279, 15786540, 19191323, 19433603, 20502448, 24909264, 30420730). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29923). 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%. Experimental studies have shown that this missense change affects PRSS1 function (PMID: 19191323, 31521106). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 11, 2023	The p.R116C pathogenic mutation (also known as c.346C>T), located in coding exon 3 of the PRSS1 gene, results from a C to T substitution at nucleotide position 346. The arginine at codon 116 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several unrelated families with hereditary pancreatitis. Furthermore, this mutation was shown to promote misfolding of the enzyme, leading to abnormal retention within cells (Kereszturi E et al. Hum Mutat. 2009; 30(4):575-582). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 17, 2024

PS3, PS4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;.;D;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.15

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.47

T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.0

.;.;L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.014

D;D;D;D

Polyphen

0.56

P;.;B;.

Vest4

0.76

MutPred

0.77

Loss of MoRF binding (P = 0.0019);.;.;.;

MVP

0.85

MPC

0.23

ClinPred

0.24

GERP RS

-0.12

Varity_R

0.43

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over