ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter) (rs72559722)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169276 SCV000220582 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2014-08-09 criteria provided, single submitter literature only
Genetic Services Laboratory, University of Chicago RCV000169276 SCV000592993 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2016-03-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000201895 SCV000612205 pathogenic not provided 2016-06-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763234 SCV000893867 pathogenic Permanent neonatal diabetes mellitus; Transient neonatal diabetes mellitus 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus 2018-10-31 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000169276 SCV000996272 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2019-03-29 criteria provided, single submitter clinical testing This nonsense variant is predicted to result in loss of normal protein function. The variant has been previously reported in ClinVar as likely pathogenic (Variation ID: 188915). This variant has been described in the heterozygous, compound heterozygous, and homozygous state in diffuse and focal congenital hyperinsulinism (PMID: 23067144, 23345197, 23301914, 26379717, 29644095). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00006 (17/272624) and thus is presumed to be rare. The c.2506C>T (p.Arg836Ter) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2506C>T (p.Arg836Ter) variant is classified as pathogenic.
Invitae RCV000201895 SCV001231207 pathogenic not provided 2020-10-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg836*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs72559722, ExAC 0.06%). This variant has been observed to be homozygous or with or without another ABCC8 variant in individuals affected with congenital hyperinsulinism (PMID: 23301914, 26379717, 29644095, 23345197, 23067144). This variant is also known as c.2509C>T, p.Arg837X in the literature. ClinVar contains an entry for this variant (Variation ID: 188915). Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169276 SCV001361436 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2019-12-16 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.2506C>T (p.Arg836X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6.1e-05 in 246774 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (6.1e-05 vs 0.0034). c.2506C>T has been reported in the literature, in compound heterozygous and homozygous state, in individuals affected with Congenital Hyperinsulinism (Tornovsky_2004, Yorifuji_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant severely impacts trafficking of the channel to the plasma membrane (it did not reach the plasma membrane at all), which in turn causes a substantial defect in channel activity (Tornovsky_2004). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Elsea Laboratory,Baylor College of Medicine RCV000763234 SCV001424286 pathogenic Permanent neonatal diabetes mellitus; Transient neonatal diabetes mellitus 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus 2020-04-01 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000201895 SCV000256810 pathogenic not provided 2015-10-07 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000169276 SCV001422873 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2020-01-22 no assertion criteria provided curation The p.Arg837Ter variant in ABCC8 has been reported in 27 individuals with congenital hyperinsulinism, segregated with disease in 2 affected relatives from 1 family ((PMID: 15579781, 30386300, 28701683, 17378627, 26379717, 25765446, 24332968, 23345197, 26740944, 21422196, 23301914, 23067144, 20943781), and has been identified in 0.03415% (12/35140) of Latino chromosomes, 0.01515% (3/19796) of East Asian chromosomes, and 0.001576% (2/126922) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559722). This variant has also been reported in ClinVar (VariationID: 188915) as likely pathogenic by Counsyl and pathogenic by The University of Chicago, Athena Diagnostics Inc., Fulgent Genetics, and The Children's Hospital of Philadelphia. In vitro functional studies provide some evidence that the p.Arg837Ter variant may slightly impact protein function (PMID: 15579781). However, these types of assays may not accurately represent biological function. The Arg at position 837 is highly conserved in mammals and evolutionary distant species, raising supporting that a change at this position may not be tolerated. This nonsense variant leads to a premature termination codon at position 837, which is predicted to lead to a truncated or absent protein. It is of note that loss of function of ABCC8 in an autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PS3_supporting (Richards 2015).
Natera, Inc. RCV001277195 SCV001464093 pathogenic Hereditary hyperinsulinism 2020-09-16 no assertion criteria provided clinical testing

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