ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.1252T>C (p.Cys418Arg) (rs67254669)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000192390 SCV000246287 likely pathogenic not specified 2017-08-24 criteria provided, single submitter clinical testing
Counsyl RCV000666629 SCV000790952 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2017-04-17 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710372 SCV000840582 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763720 SCV000894604 uncertain significance Permanent neonatal diabetes mellitus; Transient neonatal diabetes mellitus 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001102903 SCV001259602 benign Transient neonatal diabetes mellitus 2 2017-04-28 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 Clinical Services Laboratory,Illumina RCV000666629 SCV001259603 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2017-04-28 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.
Illumina Clinical Services Laboratory,Illumina RCV001102904 SCV001259604 benign Permanent neonatal diabetes mellitus 2017-04-28 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192390 SCV001338158 uncertain significance not specified 2020-02-14 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.1252T>C (p.Cys418Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00069 vs 0.0034), allowing no conclusion about variant significance. The variant has been reported in patients with congenital hyperinsulinism (CHI) in the heterozygous state, without strong evidence for causality (e.g. Aguilar-Bryan_1999, Kapoor_2013, Snider_2013). An additional occurrence was reported in a patient with atypical Fanconi-Bickel syndrome (hyperinsulinemia compared to the typical diminished insulin secretion), who also carried known pathogenic mutations in SLC2A2; the mother was also a carrier of the variant and had no history of hypoglycemia therefore, allowing no conclusions about variant significance (Hoffman_2007). Additionally, p.C418R was reported as maternally inherited in a case of focal hyperinsulinemia (Otonkoski_2006). In this patient, the authors concluded that since the variant was apparently not expressed within the focal lesion it is likely not of functional importance. Lastly, the variant was detected in a patient with MODY (Ozdemir_2018) while, it was also reported in association with type 2 diabetes (Mahajan_2018, Riveline_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available.
Baylor Genetics RCV001336810 SCV001530307 uncertain significance Type 2 diabetes mellitus 2018-10-15 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Pars Genome Lab RCV001449652 SCV001652863 uncertain significance Permanent neonatal diabetes mellitus 3 2021-05-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV001272242 SCV001454044 uncertain significance Hereditary hyperinsulinism 2020-09-16 no assertion criteria provided clinical testing

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