ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4135C>A (p.Arg1379Ser) (rs137852673)

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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 RCV000029261 SCV000051907 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.4135C>A (p.Arg1379Ser) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 205110 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.4135C>A, has been reported in the literature in at-least one individual affected with Neonatal Diabetes Mellitus (Bennett_2015) and was also observed in a patient undergoing testing for Neonatal diabetes mellitus in our laboratory (2011) who is lost to follow-up. Therefore, these data do not allow any firm conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same codon, c.4135C>T (p.Arg1379Cys), has been reported by Babenko et al (2006) and classified as pathogenic in our laboratory and in external databases (example ClinVar), suggesting this is a functionally important codon. 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. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000675131 SCV000800706 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2018-05-09 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001248973 SCV001422805 uncertain significance Monogenic diabetes 2020-01-22 no assertion criteria provided curation The p.Arg1379Ser (sometimes called p.Arg1380Ser) variant in ABCC8 has been reported in 1 individual with Monogenic Diabetes (PMID: 25555642), and has been identified in 0.009857% (3/30434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852673). 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 as a likely pathogenic variant in ClinVar (Variation ID: 35614). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional variants, each with a different amino acid change at the same position, (p.Arg1379Leu, p.Arg1379His, and p.Arg1379Cys), have been reported in association with disease in ClinVar or curated as a likely pathogenic variant or variant of uncertain significance by our study, supporting that a change at this position may not be tolerated (Variation ID: 35615). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP3 (Richards 2015).

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