Submissions for variant NM_000352.6(ABCC8):c.1384A>G (p.Ile462Val)

gnomAD frequency: 0.00097  dbSNP: rs117874766

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193705	SCV000246288	uncertain significance	not specified	2015-06-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000303097	SCV000369383	likely benign	Diabetes mellitus, transient neonatal, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000360233	SCV000369384	likely benign	Permanent neonatal diabetes mellitus	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000396751	SCV000369385	likely benign	Hyperinsulinemic hypoglycemia, familial, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics	RCV001336811	SCV001530308	uncertain significance	Type 2 diabetes mellitus	2018-01-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001546216	SCV001765695	likely benign	not provided	2023-04-07	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001546216	SCV003501853	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 462 of the ABCC8 protein (p.Ile462Val). This variant is present in population databases (rs117874766, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital hyperinsulinism (PMID: 19475716). ClinVar contains an entry for this variant (Variation ID: 210068). 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 not expected to disrupt ABCC8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002514096	SCV003644686	likely benign	Inborn genetic diseases	2022-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193705	SCV003800735	uncertain significance	not specified	2024-01-10	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1384A>G (p.Ile462Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 251358 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00088 vs 0.0034), allowing no conclusion about variant significance. c.1384A>G has been reported in the literature in individuals affected with Congenital Hyperinsulinism without strong evidence of causality (e.g. Sandal_2009, Snider_2013). These reports do not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19475716, 23275527, 27913849). ClinVar contains an entry for this variant (Variation ID: 210068). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004558438	SCV005047084	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1; Type 2 diabetes mellitus	2024-05-08	criteria provided, single submitter	clinical testing	An ABCC8 c.1384A>G (p.Ile462Val) missense variant was identified in a heterozygous state. This variant has been identified in the literature in 2 affected siblings who each inherited three ABCC8 variants, the p.Ile462Val variant and a splicing variant on the maternal allele and a nonsense variant on the paternal allele. Since both individuals had other variants expected to cause disease, the p.Ile462Val variant was interpreted as non-causal (Sandal T et al., PMID: 19475716). It has also been reported in an individual with congenital hyperinsulinism but was interpreted as non-causal (Snider KE et al., PMID: 23275527). This variant is observed on 257/282,726 alleles in the general population (gnomAD v.2.1.1). Computational predictors suggest that this variant does not impact ABCC8 function. This variant has been reported in the ClinVar database as a germline variant of uncertain significance by 5 submitters and a likely benign variant by 3 submitters (ClinVar ID: 210068). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
Natera, Inc.	RCV001279195	SCV001466278	uncertain significance	Hereditary hyperinsulinism	2020-04-03	no assertion criteria provided	clinical testing