J Med Genet. 2010 May;47(5):348-50. doi: 10.1136/jmg.2009.072751.
Autosomal dominant hereditary pancreatitis has been conclusively linked with cationic trypsinogen (PRSS1) mutations p.R122H and p.N29I, which can be found in approximately 90% of mutation-positive cases. To date, 35 additional rare or private PRSS1 variants have been identified in subjects with hereditary or sporadic, idiopathic chronic pancreatitis. Despite the lack of sufficient genetic and functional evidence, many of these rare variants have been labelled as pancreatitis associated. This problematic trend is notably illustrated by two recent studies that classified the p.A121T PRSS1 variant as pancreatitis associated, in large part owing to its intimate proximity to arginine-122, the residue affected by the disease causing p.R122H mutation.
Here we demonstrate that the p.A121T variant is functionally innocuous and shows no verifiable association with hereditary pancreatitis, on the basis of the available inconclusive data.
This case cautions that assignment of clinical relevance to rare PRSS1 variants should not be based on a perceived analogy with genuine disease causing PRSS1 mutations, and further studies are required to prove or rule out possible low penetrance causality of rare PRSS1 variants.
常染色体显性遗传性胰腺炎与阳离子胰蛋白酶原（PRSS1）突变 p.R122H 和 p.N29I 密切相关，这两种突变可在大约 90%的突变阳性病例中发现。迄今为止，在遗传性或散发性、特发性慢性胰腺炎患者中已发现 35 种其他罕见或个体特异性的 PRSS1 变体。尽管缺乏充分的遗传和功能证据，但许多这些罕见变体已被标记为与胰腺炎相关。这种有问题的趋势在最近的两项研究中得到了显著体现，这两项研究将 p.A121T PRSS1 变体归类为与胰腺炎相关，主要是因为它与精氨酸 122 非常接近，而该残基受导致疾病的 p.R122H 突变的影响。
在这里，我们证明基于现有不确定的数据，p.A121T 变体在功能上是无害的，与遗传性胰腺炎没有可验证的关联。
该病例提醒我们，不应基于与真正致病的 PRSS1 突变的可感知类比，将临床相关性赋予罕见的 PRSS1 变体，需要进一步研究来证明或排除罕见的 PRSS1 变体可能存在低外显率的因果关系。
