ClinVar Miner

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

gnomAD frequency: 0.00072  dbSNP: rs138687850
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Total submissions: 9
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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 Women's Health, 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.
Invitae RCV002056831 SCV002396520 likely benign not provided 2021-12-15 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.
Natera, Inc. RCV001278414 SCV001465427 uncertain significance Hereditary hyperinsulinism 2020-10-21 no assertion criteria provided clinical testing

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