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

gnomAD frequency: 0.00272  dbSNP: rs58241708

Total submissions: 12

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