ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4486G>A (p.Val1496Met)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003236417 SCV003934472 uncertain significance not specified 2023-05-03 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.4486G>A (p.Val1496Met) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 8e-06 in 251366 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4486G>A has been reported in the literature association with Hyperinsulinism, however authors did not provide strong evidence for causality (example: De Franco_2020). This report does not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32027066, 32041611). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003321985 SCV004026525 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2023-08-16 criteria provided, single submitter curation The p.Val1496Met variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 33688939, 33688939), and has been identified in 0.002% (2/113674) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs377696470). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Val1496Met variant is pathogenic (PMID: 33688939). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val1496Met variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting (Richards 2015).

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