Submissions for variant NM_000352.6(ABCC8):c.343A>G (p.Met115Val)

dbSNP: rs146695489

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778903	SCV000915311	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-04-28	criteria provided, single submitter	clinical testing	The ABCC8 c.343A>G (p.Met115Val) missense variant has been reported in one study in which it is found in a compound heterozygous state with a second nonsense variant in one infant with congenital hyperinsulinism (Celik et al. 2013). The unaffected mother of the patient was a carrier of the p.Met115Val variant. The p.Met115Val variant has not been reported in association with the autosomal dominant form of hyperinsulinism. Control data are unavailable for this variant, which is reported at a frequency of 0.00206 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Met115Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive hyperinsulinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001105013	SCV001261927	uncertain significance	Permanent neonatal diabetes mellitus	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869139	SCV002290618	likely pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the ABCC8 protein (p.Met115Val). This variant is present in population databases (rs146695489, gnomAD 0.2%). This missense change has been observed in individual(s) with autosomal recessive congenital hyperinsulinism (PMID: 24080777). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632057). 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 with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265884	SCV002547983	uncertain significance	not specified	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.343A>G (p.Met115Val) results in a conservative amino acid change in 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 0.00025 in 251406 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.00025 vs 0.0034), allowing no conclusion about variant significance. c.343A>G has been reported in the literature as a compound heterozygous genotype in at least one individual affected with a diffuse form of Congenital Hyperinsulinism (example, Celik_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as benign/VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
New York Genome Center	RCV003448345	SCV004176193	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1; Diabetes mellitus, permanent neonatal 3	2023-05-03	criteria provided, single submitter	clinical testing	The inherited c.343A>G, p.(Met115Val) variant identified in the ABCC8 gene substitutes a conserved Methionine for Valine at amino acid115/1582 (exon 3/39). The c.343A>G variant is observed in 81 alleles (0.01% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 andv3.1.2, TOPMed Freeze 8, All of Us) including in 69 alleles (0.19%) in South Asian subpopulation (gnomAD v2.1.1 and v3.1.2(non-Topmed)). In silico algorithms predict this variant to be damaging to protein function (REVEL=0.706). The c.343A>G, p.(Met115Val) variant has been deposited in ClinVar as a Variant of Uncertain Significance (n=3), Likely Pathogenic (n=1), and Benign (n=1) (VarID:632057), and has been reported in compound heterozygosity with a second variant in an individual with CHI [PMID:24080777]. The p.Met115 residue is in the transmembrane domain (TMD0) of ABCC8, and nearby variants within the transmembrane domain have been reported in the literature in individuals with CHI [PMID:25201519]. Given the available evidence, the inherited c.343A>G, p.(Met115Val) variant identified in the ABCC8 gene is reported as a Variant of Uncertain Significance.