Submissions for variant NM_000352.6(ABCC8):c.805del (p.Ala269fs)

dbSNP: rs1564976749

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001818047	SCV002065902	likely pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001818047	SCV002235507	pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with autosomal recessive familial hyperinsulinism (PMID: 23275527). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1338676). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala269Profs*90) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282580	SCV002570583	likely pathogenic	Familial hyperinsulinism	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.805delG (p.Ala269ProfsX90) 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 4e-06 in 251320 control chromosomes. c.805delG has been reported in the literature in at least one individual affected with Congenital Hyperinsulinism (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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003321878	SCV004026574	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Ala269ProfsTer90 variant in ABCC8 has been previously reported in 1 individual, in the homozygous state, with hyperinsulinemic hypoglycemia (PMID: 23275527), and has been identified in 0.003% (1/34592) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs372930264). 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#: 1338676) and has been interpreted as likely pathogenic/pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Genetic Services Laboratory (University of Chicago), and Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 269 and leads to a premature termination codon 90 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, PM2_supporting, PM3_supporting (Richards 2015).
Baylor Genetics	RCV003470933	SCV004192227	pathogenic	Type 2 diabetes mellitus	2023-05-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005040405	SCV005676087	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-04-10	criteria provided, single submitter	clinical testing