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Table 2 Very rare pathologically relevant variants found in HCP in the context of four CP genes

From: Expanding ACMG variant classification guidelines into a general framework

Gene

Varianta

Number of HCP families (family description) reportedb

Reference(s)

Biological/functional consequence

gpAF (hspAF) in gnomADc

PRSS1

Trypsinogen gene triplication

5 (10 patients across 4 generationsd)

Le Maréchal et al. [27]

GoF (gene dosage) [39]

Absent

Double “gain-of-function” hybrid variant

1 (6 patients across 3 generations)

Masson et al. [75]

GoF (gene dosage plus effect of p.Asn29Ile)

Absent

c.47C > T (p.Ala16Val)

2 (4 patients across 2 generations; 3 patients across 2 generations)

Grocock et al. [76]

GoF (increased activation) [77]

Absent [78]

c.62A > C (p.Asp21Ala)

1 (5 patients across 3 generations)

Yilmaz et al. [79]

GoF (increased activation) [80]

Absent

c.63_71dup (p.Lys23_Ile24insIleAspLys

1 (3 patients across 2 generations)

Joergensen et al. [81]

GoF (increased activation) [81]

Absent

c.86A > T (p.Asn29Ile)

The second most frequent variant causing HCP [38]; in the first report, one family had 19 patients across 7 generations [82]

Gorry et al. [82]

GoF (increased activation and stability) [77]

Absent

c.86A > C (p.Asn29Thr)

1 (8 patients across 3 generations)

Dytz et al. [83]

GoF (increased activation and stability) [77]

Absent

c.116T > C (p.Val39Ala)

1 (9 patients across 3 generations)

Arduino et al. [84]

GoF (increased stability) [77]

Absent

c.311T > C (p.Leu104Pro)

2 (both having 3 patients across 3 generations)

Teich et al. [85]; Németh et al. [86]

GoP (intracellular retention and elevation of ER stress marker) [87]

Absent

c.346C > T (p.Arg116Cys)

2 (3 patients across 2 generations; 3 patients across 3 generations)

Pho-Iam et al. [88]; Kereszturi et al. [89]

GoP (intracellular retention and elevation of ER stress marker) [89]

0.00007072 (0.0007018, East Asian)

c.365G > A (p.Arg122His)

The most frequent variant causing HCP [38]; in the discovery report, one family had 20 patients across 4 generations [23]

 

GoF (increased activity) [90, 91]

0.00001194 (0.00002639, non-Finnish European)

c.365_366GC > AT (p.Arg122His)

1 (4 patients across 4 generations)

Howes et al. [92]

Same as above

Absent

CFTR

Not identified

    

SPINK1

c.27DelC (p.Ser10ValfsTer5)

1 (3 patients across 2 generations)

Le Maréchal et al. [93]

LoF (predicted complete functional loss)

0.00001197 (0.00002896, Latino/Admixed American)

c.41T > G (p.Leu14Arg)

2 (both having 3 patients across 3 generations)

Király et al. [94]

LoF (experimentally demonstrated to abolish SPINK1 secretion) [94]

Absent

Deletion of the entire gene

1 (3 patients across 2 generations)

Masson et al. [95]

LoF (predicted complete functional loss)

Absent

CTRC

Not identified

    
  1. CP chronic pancreatitis, gpAF global population allele frequency, GoF gain-of-function, GoP gain-of-proteotoxicity, HCP hereditary CP, hspAF highest subpopulation allele frequency, LoF loss-of-function
  2. aAll are heterozygous. See Table 1 for reference mRNA accession numbers
  3. bData from some original reports were reinterpreted in accordance with our working definition of HCP
  4. cIn accordance with gnomAD v2.1.1 or SVs v2.1 (https://gnomad.broadinstitute.org/) [74]
  5. dDescribed was the family with the most affected patients