LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-02
Case ID: NM_002769.5_c.365G_A_20261102_211528
Framework: ACMG/AMP 2015
Variant classification summary

NM_002769.5:c.365G>A

PRSS1  · NP_002760.1:p.(Arg122His)  · NM_002769.5
GRCh37: chr7:142459789 G>A  ·  GRCh38: chr7:142751938 G>A
Gene: PRSS1 Transcript: NM_002769.5
Final call
Likely Pathogenic
PS3 strong PM5 moderate PM2 supporting PP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PRSS1
Transcript
NM_002769.5
Protein
NP_002760.1:p.(Arg122His)
gnomAD AF
1.842849426492549e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 strong: R122H showed increased trypsin activity and substantially slower degradation than wild type in variant-specific functional studies.
2
PM5 moderate: PRSS1 p.Arg122Cys, a different missense change at residue 122, segregated with autosomal-dominant hereditary pancreatitis.
3
PM2 supporting: gnomAD v4.1 filtering group maximum FAF was 4.613e-05, below 0.0001.
4
PP1 supporting: p.Arg122His segregated with hereditary pancreatitis in five kindreds.
Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one moderate and two supporting pathogenic criteria supports Likely Pathogenic; no benign rule is satisfied.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: p.Arg122His is established, but no different nucleotide change producing the same amino-acid substitution was documented.
PMID:16791840 clinvar
PS2 Not assessed Not assessed: no documented de novo proband with confirmed maternity and paternity and no family history is available.
PS3 Met Met, strong: R122H produced 4.8-fold higher trypsin activity than wild type with 25 nM CTRC and degraded 11-fold more slowly in biochemical assays.
PMID:11097832 PMID:16791840 PMID:19453252 PMID:22539344
PS4 Not assessed Not assessed: affected and control observations are reported, but exact case counts are unavailable, preventing calculation of the required OR and 95% confidence interval.
PMID:16791840
PM1 Not assessed Not assessed: Arg122 is functionally important, but no qualifying hotspot/domain with demonstrated absence of benign variation was established.
PMID:16791840 PMID:19453252 hotspots cosmic
PM2 Met Met at Supporting: gnomAD v4.1 grpmax FAF is 4.613e-05, below the supplied PM2 threshold of 0.0001, with 29 alleles observed.
gnomad_v4 gnomad_v2
PM3 N/A Not applicable: PRSS1 hereditary pancreatitis is autosomal dominant with incomplete penetrance, whereas PM3 is limited to recessive disorders with a pathogenic variant in trans.
PMID:10204851 PMID:16791840
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Met Met at moderate strength: PRSS1 p.Arg122Cys, a different missense at residue 122, was reported to cause segregating autosomal-dominant hereditary pancreatitis.
PMID:11788572
PM6 Not assessed Not assessed: no report identifies this variant as assumed de novo in a proband without parental confirmation.
PP1 Met Met at supporting strength: the variant segregated with hereditary pancreatitis in five kindreds, including affected individuals and obligate carriers.
PMID:16791840 PMID:19453252
PP2 Not assessed Not assessed: PRSS1 missense disease mechanism is supported, but the required gene-wide low benign-missense rate was not established.
PMID:16791840 PMID:22539344 gnomad_v4
PP3 Not met Not met: missense REVEL 0.511 is below the generic PP3 supporting threshold of >=0.644.
revel
PP4 Not assessed Not assessed: the patient's phenotype and family history are not documented well enough to judge high specificity for a single genetic etiology.
PP5 Not met Not met: ClinVar has no exact-variant expert-panel classification, only laboratory submissions and aggregate Pathogenic/Likely pathogenic labels.
clinvar PMID:16791840
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.004613%, far below the 5% BA1 threshold, with 70,548 observed alleles in the highest-frequency population.
gnomad_v4 gnomad_v2
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.004613%, below the 1% BS1 default despite hereditary pancreatitis having incomplete penetrance.
gnomad_v4 gnomad_v2 PMID:10204851
BS2 Not assessed Not assessed: gnomAD reports 0 homozygotes but does not establish healthy adult carrier status, and hereditary pancreatitis has incomplete penetrance.
gnomad_v4 gnomad_v2 PMID:10204851
BS3 Not met Not met: R122H increased active trypsin generation and was degraded 11-fold more slowly than wild type, contradicting preserved protein function.
PMID:11097832 PMID:19191323 PMID:19453252 PMID:22539344
BS4 Not assessed Not assessed: no affected family member is documented to lack the variant, while available reports describe co-segregation.
PMID:16791840 PMID:19453252
BP1 Not assessed Not assessed: PRSS1 has documented pathogenic missense gain-of-function variants, but predominance of truncating disease variants was not quantified.
PMID:16791840 PMID:19453252
BP2 Not assessed Not assessed: no cis/trans phase result or second pathogenic variant is documented, and PRSS1 hereditary pancreatitis is not fully penetrant dominant.
PMID:10204851 PMID:16791840
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL 0.511 is above the generic BP4 supporting threshold of <=0.29.
revel
BP5 Not met Not met: no reviewed case documents an alternate molecular basis for the patient's disease.
BP6 Not met Not met: ClinVar records zero exact-variant expert-panel submissions and no expert-panel Benign or Likely benign classification.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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