Submissions for variant NM_000352.6(ABCC8):c.3130_3149del (p.Thr1044fs)

dbSNP: rs886041392

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000393635	SCV000329972	pathogenic	not provided	2018-05-04	criteria provided, single submitter	clinical testing	The c.3130_3149del20 pathogenic variant in the ABCC8 gene has been reported previously in the heterozygous state, as well as the compound heterozygous state, in association with congenital hyperinsulinism (Fournet et al., 2001; Bellanne-Chantelot et al., 2010). The c.3130_3149del20 variant causes a frameshift starting with codon Threonine 1044, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 63 of the new reading frame, denoted p.Thr1044LeufsX63. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3130_3149del20 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3130_3149del20 as a pathogenic variant.
Counsyl	RCV000673057	SCV000798223	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2018-03-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000673057	SCV000996138	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2018-05-01	criteria provided, single submitter	clinical testing	This variant has been previously reported in individuals with congenital hyperinsulism or familial hyperinsulinemic hypoglycemia-1 (HHF1) (MIM: 256450). It has been previously classified as pathogenic for congenital hyperinsulinism in ClinVar (rs886041392, https://www.ncbi.nlm.nih.gov/clinvar/variation/280115/) and HGMD (CD016051). This variant is present in gnomAD at 0.00081% (2/245734) and thus is presumed to be rare. This variant is predicted to create a frameshift in the protein coding sequence, leading to a truncated protein with reduced protein function. Based on the combined evidence, the c.3130_3149del20 p.Thr1044LeufsTer63 variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000393635	SCV001589659	pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1044Leufs*63) 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 (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 11395395). This variant has been reported in individual(s) with autosomal dominant familial hyperinsulinism (PMID: 24401662, 32928245); however, the role of the variant in this condition is currently unclear. This variant is also known as c.3133_3152del. ClinVar contains an entry for this variant (Variation ID: 280115). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000673057	SCV004026530	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Thr1044Leufs variant in ABCC8 has been previously reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 11395395, 20685672), and has been identified in 0.002% (2/113358) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs886041392). 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#: 280115) and has been interpreted as likely pathogenic/pathogenic by Invitae, Rady Children's Institute for Genomic Medicine (Rady Children's Hospital San Diego), GeneDx, and Counsyl. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Thr1044Leufs variant is pathogenic (PMID: 11395395). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1044 and leads to a premature termination codon 63 amino acids downstream. This alteration is then 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, PM2_supporting, PM3 (Richards 2015).
Genetics and Molecular Pathology, SA Pathology	RCV000673057	SCV004175337	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2021-08-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567821	SCV005060528	pathogenic	Type 2 diabetes mellitus	2024-03-11	criteria provided, single submitter	clinical testing