ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
29749045 Evans et al (2018) identified eight rare deleterious variants in 10 families of 479 NFCCR (Newfoundland Colorectal Cancer Registry), which are over-represented in colorectal cancer (CRC) cases compared to 400 CRC-free controls (P=0.03814). There are 7 missense variants and one putative splice altering variant. All variants are predicted deleterious by multiple in silico tools. Per authors, they ?observed evidence of moderate penetrance for these GALNT12 variants? and ?Provided strong, independent evidence for the association of GALNT12 with CRC-susceptiility. Three of the new variants (p.His101Gln, p.Ile142Thr, p.Val290Phe) demonstrated a marked loss (>2-fold reduction) of enzymatic activity (p<=0.05), p.Glu239Gln exhibited a 2 ?fold reduction (P=0.07).
19617566 Guda et al. (2009) detected seven inactivating or partially inactivating variants from germline DNA (each in an individual patient) of 272 unrelated colon cancer patients. None of the variants was detected in 192 control individuals. Of these mutations, per authors, "one changed the initiating methionine codon (M1I, ATG>ATA); one is nonsense mutation (Y395X); Five missense variant with 4 encoding inactivated enzyme (R382H, 1% activity; T491M, 2% activity; R373H, 5% activity; and R279W, 7% activity) and 1 encoding enzyme with reduced activity (D303N, 37% activity)". Enzyme activity evaluation was done by transfection study. Thus, "inactivating GALNT12 mutations are found significantly more often among colon cancer patients (p=0.044)"; "the median activity of the 7 GALNT12 variants identified in the cancer patients was 2.3%, significantly lower than the 91% median activity of the 6 GALNT12 variants found among the control cohort (P< 0.001)?. ?Germ-line GALNT12 mutations likely contribute to cancer predisposition?.
22461326 Clarke et al (2012) detected two deleterious variants in 4 probands from 118 colorectal cancer (CRC) families of unknown genetic cause. These variants were not found in 149 control individuals (P=0.0376). Three harbored a c.907G>A (p.Asp303Asn) previously reported with reduced activity to 37% of wild-type protein. One individual harbored a novel variant, c.1187A>G (p.Tyr396Cys), located in catalytic domain and predicted to be pathogenic by PolyPhen and SIFT with no functional testing data. One family (20444) of three generations with two generations available for testing showed cosegregation of c.907G>A (p.Asp303Asn) with CRC and/or adenomatous polyps. Cosegregation is not conclusive for other three families due to testing DNA unavailable or infected individuals didn?t carry the variants. While admitting that this study did not provide irrefutable evidence, the authors considered this study provided evidence to support an important role of GALNT12 variants in predisposing to CRC in unexplained hereditary CRC families.

Haploinsufficiency phenotype comments:

Through linkage study, a CRC susceptibility locus spanning 9q22.32-31.1(Gray-McGuire et al., 2010; Skoglund et al., 2006; Wiesner et al., 2003) and GALNT12 resides in the 6.5cM critical interval (markers D9S1851-D9S277) within this region (Kemp et al., 2006). Although Guda et al (2009) have shown that inactivating GALNT12 alleles are over-represented in CRC cell lines and CRC patients germline; and all reported patients carrying inactivating germline mutations developed colorectal cancer (CRC) later in life (median age: 71), and half of them were diagnosed with multiple primary epithelial tumors, including breast and colon cancers; the studies carried by Segui et al (2014) and Lorca et al (2017) (see below) rule against the role of GALNT12 variants as high-penetrance risk allele for familial CRC with unknown cause or adenomatous polyposis. But the role of GALNT12 variants as moderate or low penetrance allele in CRC cannot be ruled out. In addition, one study by Evans in 2018 showed evidence for GALNT12 as a moderate penetrance gene, although cosegregation study is available in only one family in that study and it is inconclusive. Only sequence level variants have been reported, a whole gene deletions has not been reported. Based on the data reviewed the clinical significance for haploinsufficiency in GALNT12 is unclear at this time. A nonsense mutation was identified by Guda et al (2009) and functional studies have suggested loss of function. Segui et al (2014) (24115450) detected no functionally relevant variants in 103 CRC families with unknown cause; thus supported the notation that GALNT12 is not a major high-penetrance gene for CRC predisposition. The authors commented ?Either germline mutations in GALNT12 , as a moderate-risk gene, or in other genes located within 9q22-31 linkage peak might still explain some familial CRC cases?. Lorca et al (2017) (29095867) detected the c.907G>A, p.(D303N) variants in the germline DNA of 4 cases from 183 unrelated attenuated polyposis patients. No other candidate variants were found. The results from segregation studies (3 families), LOH analyses (tumors), glycosylation pattern tests and case-control studies (451 unrelated polyposis cases vs 714 cancer-free controls) did not support the role of this variant as a high penetrance risk allele for polyposis CRC. But low-penetrance allele or modifier allele is still possible, which points to the necessity of larger sample sizes to confirm or discard the role of the variant as a low-penetrance allele.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity