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

gnomAD frequency: 0.00002  dbSNP: rs72559722

Total submissions: 16

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
Athena Diagnostics	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; Diabetes mellitus, transient neonatal, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201895	SCV001231207	pathogenic	not provided	2024-12-23	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. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This variant is present in population databases (rs72559722, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital hyperinsulinism (PMID: 23067144, 23301914, 23345197, 26379717, 29644095). This variant is also known as c.2509C>T, p.Arg837X. ClinVar contains an entry for this variant (Variation ID: 188915). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169276	SCV001422873	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg836Ter variant in ABCC8 has been reported in at least 11 individuals with congenital hyperinsulinism (PMID: 30386300, 26740944, 17378627, 26379717, 28701683, 23345197, 25765446, 23301914, 21422196), and has been identified in 0.03% (12/35140) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559722). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 188915) as pathogenic or likely pathogenic by 11 submitters. Of the 11 affected individuals, 1 of those was a homozygote and 5 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Arg836Ter variant is pathogenic (Variation ID: 188864, 939498; PMID: 26740944, 26379717, 28701683, 23345197, 25765446, 21422196). In vitro functional studies provide some evidence that the p.Arg836Ter variant may slightly impact protein function (PMID: 15579781). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 836, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3_supporting (Richards 2015).
Elsea Laboratory, Baylor College of Medicine	RCV000763234	SCV001424286	pathogenic	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus	2020-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000201895	SCV002015476	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as c.2509C>T p.(R837*); This variant is associated with the following publications: (PMID: 17378627, 20943781, 23067144, 26379717, 29644095, 24332968, 10923633, 25555642, 25525159, 23301914, 2563966, 23345197, 25765446, 10204114, 15579781, 21422196, 21968108, 25639667, 26740944, 28701683, 31019026)
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000169276	SCV002515474	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2024-05-21	criteria provided, single submitter	research	This variant is found to be a potent High impact, deleterious variant with a CADD score of 40 and sufficient recent scientific evidence for both gene and variant correlation with the condition. Hence, this variant is reclassified as Likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004555856	SCV002515475	likely pathogenic	Neonatal diabetes mellitus	2024-05-21	criteria provided, single submitter	research	This variant is found to be a potent High impact, deleterious variant with a CADD score of 40 and sufficient scientific evidence of gene-disease correlation Hence, this variant is reclassified as Likely pathogenic.
Baylor Genetics	RCV003462267	SCV004197797	pathogenic	Type 2 diabetes mellitus	2024-03-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042352	SCV005676338	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-04-06	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
Natera, Inc.	RCV001277195	SCV001464093	pathogenic	Hereditary hyperinsulinism	2020-09-16	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000169276	SCV002072037	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2021-06-21	no assertion criteria provided	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2506C>T, which results in the creation of a premature stop codon at amino acid position 836, p.Arg836*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ABCC8 protein with potentially abnormal function. This pathogenic sequence change has previously been described in a patients with both diffuse and focal ABCC8-related hyperinsulinism (PMIDs: 15579781,26379717, 25765446). Functional studies have also demonstrated that this sequence change may impact protein function (PMID: 15579781).