Submissions for variant NM_000352.6(ABCC8):c.220C>T (p.Arg74Trp)

gnomAD frequency: 0.00001  dbSNP: rs201682634

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409175	SCV000486945	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2016-09-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203709	SCV001374885	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects ABCC8 function (PMID: 17575084, 19151370, 21321069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. ClinVar contains an entry for this variant (Variation ID: 371380). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 14692646, 16429405, 24645945, 25518065). This variant has been reported in individual(s) with autosomal dominant hyperinsulinemic hypoglycemia (PMID: 24645945); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs201682634, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 74 of the ABCC8 protein (p.Arg74Trp). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002230219	SCV002511484	pathogenic	Familial hyperinsulinism	2022-04-21	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.220C>T (p.Arg74Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251388 control chromosomes (gnomAD). c.220C>T has been reported in the literature in heterozygous state in multiple patients affected with focal- (or unspecified) Congenital Hyperinsulinism (CHI), as well as in patients with diffuse CHI (Suchi_2003, Fernandez-Marmiesse_2006, Senniappan_2014, Fan_2015), and in at least one case affected with diffuse HI, the presence of another pathogenic variant (R1215Q) in trans was indicated (Suchi_2003). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated strongly reduced cell surface expression (Yan_2007, Pratt_2009, Pratt_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002502430	SCV002802735	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2022-01-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000409175	SCV004026586	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg74Trp variant in ABCC8 has been reported in 9 individuals with hyperinsulinemic hypoglycemia (PMID: 14692646, 14715863, 16357843, 16429405, 20432820, 23345197, 26740944, 24645945, 25518065), and has been identified in 0.002% (3/129106) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201682634). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 371380) and has been interpreted as pathogenic/likely pathogenic by Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Fulgent Genetics, Natera (Inc.), and Counsyl. Of the 9 affected individuals, 3 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg74Trp variant is pathogenic (PMID: 14692646, 16357843, 20432820). In vitro functional studies provide some evidence that the p.Arg74Trp variant may slightly impact protein function (PMID: 17575084). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, (p.Arg74Gln), has been reported in association with disease in the literature/ClinVar, supporting that a change at this position may not be tolerated (PMID: 9618169, 10338089, 10828824, 20685672, 23275527, 23345197, 28701683, 30352420, 36239000/Variation ID: 495834). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PM2_supporting, PS3_supporting, PP3, PM5 (Richards 2015).
Baylor Genetics	RCV003463804	SCV004204674	pathogenic	Type 2 diabetes mellitus	2023-12-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828376	SCV002081195	pathogenic	Hereditary hyperinsulinism	2021-08-18	no assertion criteria provided	clinical testing