Total submissions: 6
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 |
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, |
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, |
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, |
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 |