ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.886G>A (p.Gly296Arg) (rs148529020)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029271 SCV000051917 uncertain significance not specified 2019-02-02 criteria provided, single submitter clinical testing 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.
Counsyl RCV000675093 SCV000800622 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2017-11-09 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001249020 SCV001422927 uncertain significance Monogenic diabetes 2020-01-22 no assertion criteria provided curation The p.Gly296Arg variant in ABCC8 has been reported in 1 Chinese and 1 Pakistan individuals, in the heterozygous or compound heterozygous state, with Monogenic Diabetes (PMID: 22562119, 26839896), and has been identified in 0.004013% (1/24920) of African chromosomes, 0.003267% (1/30610) of South Asian chromosomes, and 0.001555% (2/128636) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148529020). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 35624). In vitro functional studies provide some evidence that the p.Gly296Arg variant may slightly increase protein activity (PMID: 22562119). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the L0 domain, which has been associated with changes in the K-ATP channel of the protein and diabetes (PMID: 22562119). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PM1_Supporting (Richards 2015).

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