ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.1858C>T (p.Arg620Cys)

gnomAD frequency: 0.00272  dbSNP: rs58241708
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193433 SCV000246291 likely benign not specified 2015-03-19 criteria provided, single submitter clinical testing
Counsyl RCV000671926 SCV000796962 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2018-01-05 criteria provided, single submitter clinical testing
Invitae RCV000952127 SCV001098602 likely benign not provided 2024-01-31 criteria provided, single submitter clinical testing
Mendelics RCV000671926 SCV001138234 benign Hyperinsulinemic hypoglycemia, familial, 1 2023-08-22 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV001174394 SCV001337532 benign Monogenic diabetes 2018-12-07 criteria provided, single submitter research ACMG criteria: BS2 (23 cases and 24 controls in type2diabetesgenetics.org) + BS1 (0.9% MAF in gnomAD African pop) = benign (REVEL 0.445 + PP3/8 predictors + BP4/2 predictors = conflicting evidence, not using). Variant found in 46-year old male with T2DM, not overweight, treated with SU (PMID: 22210575); Reported to cause HI of infancy (AR) in summary table in PMID 23226049
GeneDx RCV000952127 SCV001757904 likely benign not provided 2021-05-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31604004, 23275527, 28095440, 22995991, 22210575, 20849526, 10204114, 20981092, 23771920)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000193433 SCV002598613 likely benign not specified 2022-09-29 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.1858C>T (p.Arg620Cys) results in a non-conservative amino acid change in 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 251124 control chromosomes, predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1858C>T has been reported in the literature as a non-informative genotype (unclear inheritance pattern) in settings of Familial Hyperinsulinism, Adult onset Type 2 diabetes and Gestational Diabetes (example, Lang_2010, Riveleine_2012, Doddabelavangala Mruthyunjaya_2017). These report(s) 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 a predominant consensus as benign/likely benign (n=5) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000952127 SCV004562089 likely benign not provided 2023-11-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV001274301 SCV001458273 benign Hereditary hyperinsulinism 2019-12-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000952127 SCV001551133 uncertain significance not provided no assertion criteria provided clinical testing The ABCC8 p.Arg620Cys variant was identified in 2 of 378 proband chromosomes (frequency: 0.0053) from individuals or families with Maturity Onset Diabetes of the Young (MODY) or Type 2 diabetes (Doddabelavangala_2017_PMID:28095440; Riveline_2012_PMID:22210575). The variant was also identified in dbSNP (ID: rs58241708), ClinVar (classified as likely benign by Genetic Services Laboratory, University of Chicago and as a VUS by Counsyl) and LOVD 3.0. The variant was identified in control databases in 253 of 282492 chromosomes (1 homozygous) at a frequency of 0.000896 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 231 of 24964 chromosomes (freq: 0.009253), Latino in 10 of 35424 chromosomes (freq: 0.000282), Other in 2 of 7222 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10360 chromosomes (freq: 0.000193), South Asian in 5 of 30616 chromosomes (freq: 0.000163) and European (non-Finnish) in 3 of 129052 chromosomes (freq: 0.000023), while the variant was not observed in the East Asian or European (Finnish) populations. The p.Arg620 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000952127 SCV002035046 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000952127 SCV002037089 likely benign not provided no assertion criteria provided clinical testing

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