Submissions for variant NM_000352.6(ABCC8):c.3112G>A (p.Asp1038Asn)

gnomAD frequency: 0.00010  dbSNP: rs367974472

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000394844	SCV000369296	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	RCV000292832	SCV000369297	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	RCV000352427	SCV000369298	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.
Invitae	RCV002056180	SCV002343174	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002250621	SCV002520760	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 (rs367974472) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251452	SCV002520761	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 (rs367974472) in neonatal diabetes yet.
New York Genome Center	RCV000394844	SCV004046575	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2022-10-26	criteria provided, single submitter	clinical testing	The c.3112G>A variant identified in the ABCC8 gene has not been previously reported in affected individuals in the literature and has been reported in ClinVar as both a Variant of Uncertain Significance and as Likely Benign (VarID:303766). It is observed in population databases (gnomADv2.1,gnomADv3.1.2, BRAVO-TOPMed) with highest allele frequency of 1.05e-4 (16 heterozygotes, 0 homozygotes, gnomADv3.1.2) suggesting it is not a common benign variant in the populations represented in those databases. The c.3112G>A variant is located within exon 25 of this 39-exon gene and is predicted to substitute a moderately conserved Aspartic Acid for Asparagine at amino acid 1038/1582 p.(Asp1038Asn) within the ABC transmembrane type-1,2 (UniProtKB:Q09428). In silico algorithms do not predict this variant to significantly affect the canonical protein (REVEL=0.397). Based on the available evidence, the c.3112G>Ap.(Asp1038Asn) variant identified in the ABCC8 gene is reported as a Variant of Uncertain Significance.
Natera, Inc.	RCV001278400	SCV001465413	uncertain significance	Hereditary hyperinsulinism	2020-04-10	no assertion criteria provided	clinical testing