Submissions for variant NM_000352.6(ABCC8):c.3053C>T (p.Ser1018Leu)

gnomAD frequency: 0.00001  dbSNP: rs775087568

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000394821	SCV000369299	uncertain significance	Permanent neonatal diabetes mellitus	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000298394	SCV000369300	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000353216	SCV000369301	uncertain significance	Diabetes mellitus, transient neonatal, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812789	SCV002048094	uncertain significance	not provided	2021-11-16	criteria provided, single submitter	clinical testing	The ABCC8 c.3053C>T; p.Ser1018Leu variant (rs775087568) is reported in an individual undergoing genetic testing for maturity-onset diabetes of the young (De Santana 2019). The variant is reported in the ClinVar database (Variation ID: 303767) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 1018 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.482). Due to limited information, the clinical significance of the p.Ser1018Leu variant is uncertain at this time. References: De Santana LS et al. Targeted sequencing identifies novel variants in common and rare MODY genes. Mol Genet Genomic Med. 2019 Dec;7(12):e962. PMID: 31595705.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001812789	SCV003450582	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1018 of the ABCC8 protein (p.Ser1018Leu). This variant is present in population databases (rs775087568, gnomAD 0.003%). This missense change has been observed in individual(s) with diabetes (PMID: 31595705, 32027066). ClinVar contains an entry for this variant (Variation ID: 303767). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.