ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.3413C>T (p.Thr1138Met)

gnomAD frequency: 0.00008  dbSNP: rs201351976
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000991471 SCV001142887 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing
GeneDx RCV000991471 SCV001986305 uncertain significance not provided 2020-11-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with familial hyperinsulinism and reported as a complex allele with the R1394H variant (Nestorowicz et al., 1998); however, in vitro functional studies demonstrate R1394H results in a damaging effect on function and T1138M has no significant effect compared to wildtype, suggesting R1394H is the causative variant (Shyng et al., 1998); This variant is associated with the following publications: (PMID: 9648840, 9618169)
Genetic Services Laboratory, University of Chicago RCV001819697 SCV002070464 uncertain significance not specified 2019-07-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001819697 SCV002555820 uncertain significance not specified 2022-06-10 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.3413C>T (p.Thr1138Met) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 242956 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3413C>T has been reported in the literature as part of a complex allele with c.4178G>A [p.Arg1393His] in at least one individual affected with Familial Hyperinsulinism (Nestorowicz_1998). This report does not provide unequivocal conclusion about association of the variant with Familial Hyperinsulinism. A functional report from the same lab using transfected COSm6 cells determined that the variant of interest had mild effects on K-ATP channel activity (Shyng_1998). Shyng_1998 also determined that the second variant, p.Arg1393His, was nonfunctional, suggesting p.Arg1393His is the primary cause of hyperinsulinism in the patient identified in Nestorowicz_1998. Four ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002488083 SCV002784172 uncertain significance Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2022-03-05 criteria provided, single submitter clinical testing
Natera, Inc. RCV001277190 SCV001464088 uncertain significance Hereditary hyperinsulinism 2020-09-16 no assertion criteria provided clinical testing

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