Submissions for variant NM_000352.6(ABCC8):c.2176G>A (p.Ala726Thr)

gnomAD frequency: 0.00072  dbSNP: rs138687850

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501008	SCV000592986	likely benign	not specified	2021-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763719	SCV000894603	uncertain significance	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102697	SCV001259382	benign	Diabetes mellitus, transient neonatal, 2	2017-08-31	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001102698	SCV001259383	uncertain significance	Permanent neonatal diabetes mellitus	2017-08-31	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001102699	SCV001259384	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-08-31	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Myriad Genetics, Inc.	RCV001102699	SCV002060111	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2021-11-19	criteria provided, single submitter	clinical testing	NM_000352.3(ABCC8):c.2176G>A(A726T) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. A726T has been observed in cases with relevant disease (PMID: 23345197, 24401662, 26758964). Functional assessments of this variant are not available in the literature. A726T has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.2176G>A(A726T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002056831	SCV002396520	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501008	SCV002547982	uncertain significance	not specified	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.2176G>A (p.Ala726Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.00045 vs 0.0034), allowing no conclusion about variant significance. c.2176G>A has been reported in the literature in individuals affected with Familial Hyperinsulinism or pulmonary arterial hypertension. These reports do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=3, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002056831	SCV004025618	uncertain significance	not provided	2024-05-02	criteria provided, single submitter	clinical testing	Identified in additional patients with congenital hyperinsulinism, however, a second ABCC8 variant was not identified (PMID: 21378087, 23345197, 24401662); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32934261, 24401662, 23345197, 32027066, 21378087, 26758964)
Natera, Inc.	RCV001278414	SCV001465427	uncertain significance	Hereditary hyperinsulinism	2020-10-21	no assertion criteria provided	clinical testing