ClinVar Genomic variation as it relates to human health

Variant summary: ABCC8 c.1634delT (p.Phe545SerfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.3e-06 in 157950 control chromosomes (gnomAD). c.1634delT has been reported in the literature in individuals affected with Congenital Hyperinsulinism (example: Suchi_2006, Snider_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Phe545Serfs*2) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with focal congenital hyperinsulinism (PMID: 16357843). This variant is also known as 1631del t. ClinVar contains an entry for this variant (Variation ID: 446765). For these reasons, this variant has been classified as Pathogenic.

The c.1634delT (p.F545Sfs*2) alteration, located in exon 11 (coding exon 11) of the ABCC8 gene, consists of a deletion of one nucleotide at position 1634, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is unlikely to be causative of ABCC8-related diabetes mellitus; however, it would be expected to be causative of familial hyperinsulinemic hypoglycemia based on mechanism of disease. This mutation was identified in a cohort of individuals with congenital hyperinsulinism; however, details were limited (Snider, 2013). Based on the available evidence, this alteration is classified as pathogenic.

This variant is found to be a potent moderate impact, variant with a 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.

This variant is found to be a potent moderate impact variant with a 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

The p.Phe545SerfsTer2 variant in ABCC8 has been previously reported in at least 2 individuals with hyperinsulinemic hypoglycemia (PMID: 16357843, 23275527), and has been identified in 0.002% (1/24796) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1260178539). 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#: 446765) and has been interpreted as pathogenic by five sources. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Phe545SerfsTer2 variant is pathogenic (PMID: 16357843). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 545 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. 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: PVS1, PM3, PM2_supporting (Richards 2015).