Submissions for variant NM_000352.6(ABCC8):c.3989-9G>A

gnomAD frequency: 0.00019  dbSNP: rs151344623

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000144995	SCV000192031	pathogenic	not provided	2013-07-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000144995	SCV000229594	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000144995	SCV000612213	pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590487	SCV000696590	pathogenic	Familial hyperinsulinism	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The ABCC8 variant, c.3989-9G>A (alternatively also known as 3992-9G>A) involves the alteration of a non-conserved intronic nucleotide in intron 32. Mutation taster predicts a disease-causing outcome for this variant. While Human Splicing Finder predicts this variant to form a cryptic splice acceptor site, other four splice prediction tools predict no significant impact on normal splicing. Functional study shows that this variant leads to aberrant splicing, resulting in a 7-bp addition, a 20-bp deletion, or 30-bp deletion of exon 32 that encodes NBF-2 (nucleotide binding fold 2) of the protein (Thomas_1995). This variant was found in 373/164074 control chromosomes including ExAC at a frequency of 0.0022734, which does not exceed the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (0.0033541). This variant is a known common pathogenic variant causing congenital hyperinsulinism (CH). In Ashkenazi population, c.39899G>A and p.F1387del are the two most common CH-associated ABCC8 mutations (Nestorowicz_1998, Glaser_2011). Carrier rate of this mutation in Ashkenazi general population is 1:60 (Glaser_2011). In GeneReviews, proportion of familial CH attributed to these two mutations is estimated to be nearly 45%. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000144995	SCV000954424	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 32 of the ABCC8 gene. It does not directly change the encoded amino acid sequence of the ABCC8 protein. This variant is present in population databases (rs151344623, gnomAD 0.6%). This variant has been observed in individual(s) with autosomal recessive familial hyperinsulinism (PMID: 7716548, 27754802). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8923011, 21716120). This variant is also known as 3992–9g→a. ClinVar contains an entry for this variant (Variation ID: 9088). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 7716548). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000009656	SCV001194093	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-12-26	criteria provided, single submitter	clinical testing	NM_000352.3(ABCC8):c.3989-9G>A is classified as pathogenic in the context of ABCC8-related familial hyperinsulinism. Sources cited for classification include the following: PMID 10447255, 7716548, 23345197, 11999683, 11272143, 24401662, 15579781, 21851374, 16860127 and 8923011. Classification of NM_000352.3(ABCC8):c.3989-9G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics	RCV001267446	SCV001445627	pathogenic	Inborn genetic diseases	2022-05-04	criteria provided, single submitter	clinical testing	The c.3989-9G>A intronic alteration results from a G to A substitution 9 nucleotides before coding exon 33 of the ABCC8 gene. Based on the available evidence, the ABCC8 c.3989-9G>A alteration is classified as pathogenic for familial hyperinsulinemic hypoglycemia, but is unlikely to be causative of autosomal dominant ABCC8-related diabetes mellitus. This alteration has been reported in the homozygous and compound heterozygous states and in the heterozygous state on the paternal allele in multiple individuals with congenital hyperinsulinemic hypoglycemia (Del Roio Liberatore, 2015; Glaser, 2011; Gutgold, 2017; Nestorowicz, 1996; Thomas, 1995). This is also a common founder mutation in the Ashkenazi Jewish population (Glaser, 2011; Nestorowicz, 1996). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000144995	SCV001874140	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	Published functional studies suggest that c.3989-9G>A activates a preexisting cryptic 3splice site within exon 33, resulting in out-of-frame product (Saint-Martin et al., 2021); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25972930, 7716548, 8923011, 20672374, 27754802, 21716120, 25306193, 31980526, 31589614, 33726816, 33410562)
Revvity Omics, Revvity	RCV000144995	SCV002018628	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing
3billion	RCV000009656	SCV002521684	pathogenic	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: 0.029%). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.70). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25306193) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 27754802, 7716548). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009088). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
New York Genome Center	RCV002467491	SCV002764503	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1; Diabetes mellitus, permanent neonatal 3	2022-01-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000009656	SCV004026518	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.3989-9G>A variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 25306193, 25972930, 16429405, 16860127, 27175728, 17378627, 11272143, 27754802), and has been identified In 0.6% (62/10366) or Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs151344623). 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 (Variation ID: 9088) and has been interpreted as pathogenic by multiple sources. Of the many affected individuals, at least 3 were compound heterozygotes that carried a reported pathogenic variant in trans, and 4 of those were homozygotes, which increases the likelihood that the c.3989-9G>A variant is pathogenic (Variation ID: 188864, 9096; PMID: 16429405, 16860127, 17378627). RNAseq analysis performed on affected tissue shows a deletion of the first 20 nucleotides of exon 33 (PMID: 33410562). This variant is located in the 3’ splice region. 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, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PS3, PP3 (Richards 2015).
Baylor Genetics	RCV003473069	SCV004194783	pathogenic	Type 2 diabetes mellitus	2023-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904825	SCV004727180	pathogenic	ABCC8-related condition	2024-02-09	criteria provided, single submitter	clinical testing	The ABCC8 c.3989-9G>A variant is predicted to interfere with splicing. This variant has been previously reported to be pathogenic for persistent hyperinsulinemic hypoglycemia due to defective splicing (Thomas et al. 1995. PubMed ID: 7716548; Nestorowicz et al. 1996. PubMed ID: 8923011). In Family 4 of the Thomas et al. study, this variant occurred in the homozygous state in two affected siblings and was heterozygous in both unaffected parents. In the Nestorowicz et al. study, out of the 23 probands who had this variant, 11 were homozygotes and 12 were heterozygotes. This variant is reported in 0.60% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In summary, this variant is interpreted as pathogenic.
OMIM	RCV000009656	SCV000029874	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	1999-01-01	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000144995	SCV000256803	pathogenic	not provided	2015-10-07	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000590487	SCV001142418	pathogenic	Familial hyperinsulinism	2020-01-06	no assertion criteria provided	curation	NG_008867.1(NM_001287174.1):c.3992-9G>A in the ABCC8 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been observed to segregate with familial hyperinsulinism and affect RNA splicing (PMID: 7716548). In addition, Gutgold et al. reported a male with recurrent hypoglycemia episodes and revealed a homozygosity for c.3992-9G>A (PMID: 27754802). Experimental studies have shown that this intronic change alters ABCC8 splicing (PMID: 7716548). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PM3; PP4.
Natera, Inc.	RCV001277185	SCV001464083	pathogenic	Hereditary hyperinsulinism	2020-09-16	no assertion criteria provided	clinical testing