Submissions for variant NM_000352.6(ABCC8):c.4477C>T (p.Arg1493Trp)

gnomAD frequency: 0.00001  dbSNP: rs28936371

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000009664	SCV000220188	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2014-03-24	criteria provided, single submitter	literature only
Athena Diagnostics	RCV000710390	SCV000840600	pathogenic	not provided	2017-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710390	SCV001221921	pathogenic	not provided	2023-12-04	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 1493 of the ABCC8 protein (p.Arg1493Trp). This variant is present in population databases (rs28936371, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive diffuse or focal hyperinsulinism (PMID: 9769320, 15579781, 30186238). This variant is also known as R1494W. ClinVar contains an entry for this variant (Variation ID: 9096). 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 95%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 15579781). This variant disrupts the p.Arg1493 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 10426386), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000009664	SCV002513288	uncertain risk allele	Hyperinsulinemic hypoglycemia, familial, 1	2024-05-11	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 29.3 and sufficient scientific evidence to support gene-disease correlation. This is found more frequently in congenital Hyperinsulinism cases as per recent evidence as well. However, since this is not a high impact variant and has limited evidence, this variant is reclassified as Uncertain risk allele only.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004549354	SCV002513289	uncertain risk allele	Diabetes mellitus, transient neonatal, 2	2024-05-11	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 29.3 and sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000009664	SCV004026546	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg1493Trp variant in ABCC8 has been reported in at least 9 individuals with hyperinsulinemic hypoglycemia (PMID: 30186238, 33688939, 10202168, 10426386, 19475716, 9769320, 15579781), segregated with disease in 2 affected relatives from 2 families (PMID: 19475716), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28936371). 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#: 9096) and has been interpreted as pathogenic or likely pathogenic by multiple sources. Of the 9 affected individuals, at least 4 were compound heterozygotes that carried a reported pathogenic variants in trans, which increases the likelihood that the p.Arg1493Trp variant is pathogenic (PMID: 30186238, 9769320). In vitro functional studies provide some evidence that the p.Arg1493Trp variant may slightly impact protein function (PMID: 15579781). 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very-strong, PP3, PP2_supporting, PS3_supporting, PP1 (Richards 2015).
Baylor Genetics	RCV003466844	SCV004194318	pathogenic	Type 2 diabetes mellitus	2023-09-08	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000009664	SCV005051721	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2024-02-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV005042019	SCV005676654	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-04-01	criteria provided, single submitter	clinical testing
OMIM	RCV000009664	SCV000029882	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	1998-10-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831558	SCV002085270	pathogenic	Hereditary hyperinsulinism	2021-05-02	no assertion criteria provided	clinical testing