Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590221 | SCV000698173 | uncertain significance | not provided | 2017-07-31 | criteria provided, single submitter | clinical testing | Variant summary: The SPINK1 c.1A>T (p.Met1Leu) variant involves the alteration of a conserved nucleotide and the start codon. There is no second Met in SPINK1 protein, suggesting the abolishment of the Met1 is likely to be damaging. In consistency with this prediction, 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 119498 control chromosomes and has been reported in at least one patient with chronic pancreatitis with co-occurrence of a pathogenic variant SPINK1 p.Asn34Ser (Masson_2008). Another start codon loss, p.Met1Thr, has been reported to associate with chronic pancreatitis (HGMD database). Taken together, this variant is classified as VUS-possibly pathogenic until more information becomes available. |
| ARUP Laboratories, |
RCV000590221 | SCV000884573 | pathogenic | not provided | 2017-07-03 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000987609 | SCV001136992 | likely pathogenic | Hereditary pancreatitis | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000987609 | SCV003247658 | likely pathogenic | Hereditary pancreatitis | 2023-02-04 | criteria provided, single submitter | clinical testing | 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. ClinVar contains an entry for this variant (Variation ID: 496201). Disruption of the initiator codon has been observed in individual(s) with chronic pancreatitis (PMID: 10835640,18172691). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPINK1 mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK1 are known to be pathogenic (PMID: 22572128,17681820). |
| Ambry Genetics | RCV000987609 | SCV003870826 | likely pathogenic | Hereditary pancreatitis | 2024-08-19 | criteria provided, single submitter | clinical testing | The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the SPINK1 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was reported in a patient with idiopathic chronic pancreatitis and was seen in conjunction with SPINK1 p.N34S (phase unknown) and CTRC c.494-10C>T (Masson E et al. Hum Genet 2008 Feb;123(1):83-91). A different variant that also abolishes the initiation codon was identified in a patient with hereditary chronic pancreatitis (Witt H et a. Nat Genet 2000 Jun;25(2):213-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |