Submissions for variant NM_000352.6(ABCC8):c.2116+2T>C

gnomAD frequency: 0.00001  dbSNP: rs786204676

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169482	SCV000220933	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2014-12-04	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376866	SCV001574052	likely pathogenic	not provided	2023-06-04	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs786204676, gnomAD 0.002%). This sequence change affects a donor splice site in intron 15 of the ABCC8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). Disruption of this splice site has been observed in individual(s) with congenital hyperinsulinism (PMID: 20685672). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189078).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251436	SCV002522267	uncertain risk allele	Maturity onset diabetes mellitus in young	2024-05-27	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 29.3 and sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004556759	SCV002522268	uncertain risk allele	Neonatal diabetes mellitus	2024-05-27	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 29.3 and sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169482	SCV004026548	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.2116+2T>C variant in ABCC8 has been reported in at least 1 individual with hyperinsulinemic hypoglycemia (PMID: 20685672, 22048969), and has been identified in 0.002% (2/113270) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs786204676). 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: 189078) and has been interpreted as likely pathogenic by Counsyl and Invitae, and as a variant of uncertain significance by Clinical Genomics (Uppaluri K&H Personalized Medicine Clinic). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).