ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs766431403
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667948 SCV000792477 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2017-06-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001220536 SCV001392531 pathogenic not provided 2021-10-22 criteria provided, single submitter clinical testing 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 variant is present in population databases (rs766431403, ExAC 0.01%). 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).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV004556811 SCV002513535 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 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 criteria provided, single submitter 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
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

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