ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.3640C>T (p.Arg1214Trp)

gnomAD frequency: 0.00004  dbSNP: rs139964066
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000223959 SCV000281360 pathogenic not provided 2014-08-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588494 SCV000696589 pathogenic Familial hyperinsulinism 2017-01-12 criteria provided, single submitter clinical testing Variant summary: The ABCC8 c.3640C>T (p.Arg1214Trp also known as p.Arg1215Trp) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/121412 (1/15174), which does not exceed the estimated maximal expected allele frequency for a pathogenic ABCC8 variant of 1/298. Multiple publications cite the variant in affected individuals, who are compound heterozygotes. In addition, multiple clinical diagnostic laboratory classifies this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000666191 SCV000790442 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2017-03-21 criteria provided, single submitter clinical testing
Invitae RCV000223959 SCV001219153 pathogenic not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1214 of the ABCC8 protein (p.Arg1214Trp). This variant is present in population databases (rs139964066, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive congenital hyperinsulinemia (PMID: 17575084, 23275527, 24401662, 24937539, 26180531, 28442472). This variant is also known as p.Arg1215Trp. ClinVar contains an entry for this variant (Variation ID: 235633). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg1214 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14692646, 15562009, 20685672, 23275527). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003469115 SCV004197151 pathogenic Type 2 diabetes mellitus 2023-10-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV001828097 SCV002075583 pathogenic Hereditary hyperinsulinism 2020-07-13 no assertion criteria provided clinical testing

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