ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.221G>A (p.Arg74Gln) (rs72559734)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586584 SCV000696585 pathogenic Familial hyperinsulinism 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The ABCC8 c.221G>A (p.Arg74Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found at a low frequency in the control population (1/121894 control chromosomes). The variant was reported in the literature in multiple patients with congenital hyperinsulinemia (CHI) both in the homozgous and compound heterozygous states. Taken together, this variant is classified as pathogenic.
Athena Diagnostics Inc RCV000710375 SCV000840585 pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763236 SCV000893869 pathogenic 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
Invitae RCV000710375 SCV001389945 likely pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 74 of the ABCC8 protein (p.Arg74Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs72559734, ExAC 0.002%). This variant has been observed in individual(s) with congenital hyperinsulinism (PMID: 9618169, 21992908, 23345197). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 495834). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg74 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 16429405, 24645945), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000984140 SCV001132111 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2019-02-26 no assertion criteria provided clinical testing

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