ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.946G>A (p.Gly316Arg)

gnomAD frequency: 0.00001  dbSNP: rs1201126343
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion RCV002251095 SCV002521500 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ABCC8 related disorder (PMID: 26545620). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV002496184 SCV002784768 uncertain significance Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2021-10-14 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002251095 SCV004026571 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2023-08-16 criteria provided, single submitter curation The p.Gly316Arg variant in ABCC8 has been previously reported in 5 individuals with hyperinsulinemic hypoglycemia (PMID: 34253504, 26545620, Mohamed 2016, Han 2016), and has been seen in 0.004% (1/24924) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs1201126343). 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. This variant has also been reported in ClinVar (Variation ID: 687413) and has been interpreted as a variant of uncertain significance by 3billion. Of the 5 affected individuals, 3 were compound heterozygotes that carried reported likely pathogenic variants in trans, which increases the likelihood that the p.Gly316Arg variant is pathogenic (PMID: 34253504, Mohamed 2016). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PP3, PM2_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003403755 SCV004122672 likely pathogenic Familial hyperinsulinism 2023-10-10 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.946G>A (p.Gly316Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 251086 control chromosomes. c.946G>A has been reported in the literature in homozygous and compound heterozygous individuals (Kagan_2022, Nvoa-Medina_2021) and also in heterozygous individuals (Wu_2016, Craigie_2018) affected with Congenital Hyperinsulinism. These data indicate that the variant is likely to be associated with disease. 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: 30386300, 31291970, 36699461, 31525223, 34253504, 26545620). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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