Submissions for variant NM_000352.6(ABCC8):c.2921-1G>A

dbSNP: rs772682942

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797020	SCV000936558	likely pathogenic	not provided	2021-02-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 24 of the ABCC8 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with ABCC8-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251516	SCV002521942	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 variant with a CADD score of 33 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
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004556823	SCV002521943	uncertain risk allele	Neonatal diabetes mellitus	2024-05-27	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, variant with a CADD score of 33 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	RCV003321738	SCV004026535	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.2921-1G>A variant in ABCC8 has been reported in 1 individual, in the homozygous state, with hyperinsulinemic hypoglycemia (PMID: 32027066), and has been identified in 0.003% (1/30284) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772682942). 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: 643339) and has been interpreted as likely pathogenic by Invitae and as a variant of uncertain significance by Uppaluri K&H Personalized Medicine Clinic. This variant is located in the 5' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 2 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_supporting, PM2_supporting, PVS1 (Richards 2015).