Submissions for variant NM_000352.6(ABCC8):c.1537G>A (p.Ala513Thr)

gnomAD frequency: 0.00005  dbSNP: rs761748692

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000280602	SCV000369380	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-01-13	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	RCV000337979	SCV000369381	likely benign	Diabetes mellitus, transient neonatal, 2	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000396760	SCV000369382	uncertain significance	Permanent neonatal diabetes mellitus	2018-01-13	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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002266950	SCV002522393	uncertain significance	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs761748692) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002266951	SCV002522394	uncertain significance	Transitory neonatal diabetes mellitus		criteria provided, single submitter	research	Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs761748692) in neonatal diabetes yet.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002520703	SCV003505761	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 513 of the ABCC8 protein (p.Ala513Thr). This variant is present in population databases (rs761748692, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of autosomal dominant diabetes (PMID: 32027066). ClinVar contains an entry for this variant (Variation ID: 303783). 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. 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.
Revvity Omics, Revvity	RCV002520703	SCV003824364	uncertain significance	not provided	2022-04-04	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000280602	SCV003925367	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2022-03-25	criteria provided, single submitter	clinical testing	The c.1537G>A (p.Ala513Thr) variant identified in the ABCC8 gene is the substitution of a well conserved Alanine for Threonine at amino acid 513/1582 (exon 10/39). This variant is found with low frequency in gnomAD(v3.1.2) (7 heterozygotes, 0 homozygotes; allele frequency: 4.601e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (SIFT; score:0.004) and Pathogenic (REVEL;score:0.8119) to the function of the canonical transcript. This variant is reported as both a Variant of Uncertain Significance and Likely Benign in ClinVar (VarID:303783), and has been reported in three individuals with diabetes [PMID:31291970, 33046911, 32027066], though with uncertain clinical significance and in one family did not segregate with disease [PMID:32027066]. While it is identified with low frequency in population databases and identified in several affected individuals in the literature, its lack of segregation in one of those families and unclear functional consequence results in the classification of the heterozygous c.1537G>A (p.Ala513Thr) variant in the ABCC8 gene as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004537710	SCV004730384	uncertain significance	ABCC8-related disorder	2024-02-22	no assertion criteria provided	clinical testing	The ABCC8 c.1537G>A variant is predicted to result in the amino acid substitution p.Ala513Thr. This variant was reported in an individual with diabetes, who inherited this variant from the unaffected mother (De Franco et al 2020. PubMed ID: 32027066). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.