ClinVar

Description

Variant summary: The variant, ABCC8 c.886G>A (p.Gly296Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277752 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.886G>A has been reported in the literature in individuals affected with Neonatal Diabetes Mellitus/diabetes mellitus of infancy (Cao_2016, Lin_2012). At-least one of these reports included an individual with Transient Neonatal Diabetes Mellitus (subtype T, Cao_2016) in whom the variant was inherited from the mother whose clinical status was not provided. These reports do not provide unequivocal conclusions about association of the variant with the disease. The variant was found to be causative to NDM in a compound heterozygous state (Lin_2012). The authors reported a recessive contribution of this variant in compound heterozygosity as manifesting in increased K-ATP channel conductance. At least one publication reports experimental evidence evaluating an impact on protein function (Lin_2012), however, this does not allow convincing conclusions about the variant effect under the presumed autosomal dominant mode of inheritance of NDM due to gain of function mutations in ABCC8. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least three new reports indicating its presence in individuals diagnosed with NDM or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until additional functional impact and unequivocal co-segregation with disease in additional families/individuals with NDM is obtainedthe variant was classified as uncertain significance.