Submissions for variant NM_000352.6(ABCC8):c.3868-1G>A

gnomAD frequency: 0.00001  dbSNP: rs766431403

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001220536	SCV001392531	pathogenic	not provided	2021-10-22	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs766431403, ExAC 0.01%). For these reasons, this variant has been classified as 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: 552652). This variant is also known as c.3871-1G>A. Disruption of this splice site has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 22876564, 23345197). This sequence change affects an acceptor splice site in intron 31 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).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000667948	SCV004026520	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.3868-1G>A variant in ABCC8 has been reported in at least 2 individuals with hyperinsulinemic hypoglycemia (PMID: 23345197, 22876564), and has been identified in 0.01% (3/30600) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766431403). 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: 552652) and has been interpreted as pathogenic by Counsyl and Invitae and as a variant of uncertain significance by Clinical Genomics (Uppaluri K&H Personalized Medicine Clinic). Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the c.3868-1G>A variant is pathogenic (PMID: 22876564, 23345197). This variant is located in the 3' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 145 bases from the intron-exon boundary, providing evidence that this variant may cause a frameshift and lead to a premature termination codon downstream. This alteration is then predicted to lead to a truncated or absent protein. However, 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, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3, PM2_supporting, PVS1 (Richards 2015).
Baylor Genetics	RCV003459592	SCV004207939	pathogenic	Type 2 diabetes mellitus	2023-02-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005049641	SCV005681078	likely pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005418286	SCV006085921	pathogenic	Familial hyperinsulinism	2025-05-19	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.3868-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ABCC8 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 247796 control chromosomes. c.3868-1G>A has been observed in individual(s) affected with Congenital hyperinsulinism (example: Kapoor_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 552652). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000667948	SCV000792477	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2017-06-26	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004556811	SCV002513535	uncertain risk allele	Neonatal diabetes mellitus	2024-05-27	flagged submission	research	This variant is found to be a potent moderate impact, variant with a CADD score of 34 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	RCV002246134	SCV002513536	uncertain risk allele	Maturity onset diabetes mellitus in young	2024-05-27	flagged submission	research	This variant is found to be a potent moderate impact variant with a CADD score of 34 and sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele