Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000352.6(ABCC8):c.1284_1285insTAATCTGGTTGCCATCGACACCAATCAGCTC(p.Met429Ter) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L428L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-17448563-T-TGAGCTGATTGGTGTCGATGGCAACCAGATTA is Pathogenic according to our data. Variant chr11-17448563-T-TGAGCTGATTGGTGTCGATGGCAACCAGATTA is described in ClinVar as [Pathogenic]. Clinvar id is 434055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Genetic Services Laboratory, University of Chicago
Mar 01, 2016
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Pathogenic, criteria provided, single submitter
curation
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Aug 16, 2023
The Met429Ter variant in ABCC8 has been reported in at least 5 individuals with congenital hyperinsulinism (PMID: 25201519, 23345197, 23275527), and has been identified in 0.004% (4/113754) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs768951263). 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 (VariationID: 434056) as pathogenic by Invitae, Genetic Services Laboratory (University of Chicago), Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Natera Inc. Of the 5 affected individuals, at least 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the Met429Ter variant is pathogenic (Variation ID: 370604; PMID: 23275527). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 429 and leads to a premature termination codon 1 amino acid 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). -
Familial hyperinsulinism Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 27, 2022
Variant summary: ABCC8 c.1254_1284dup31 (p.Met429X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251476 control chromosomes (gnomAD). c.1254_1284dup31 has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism (Banerjee_2011, Kapoor_2013, Snider_2013, Arya_2014, Demirbilek_2014). 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. Three ClinVar submitters have assessed the variant since 2014: all three classified 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.Met429*) 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). This variant is present in population databases (rs768951263, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 25201519). ClinVar contains an entry for this variant (Variation ID: 434055). For these reasons, this variant has been classified as Pathogenic. -