Submissions for variant NM_000352.6(ABCC8):c.3989-10C>T

gnomAD frequency: 0.00001  dbSNP: rs373737642

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000279547	SCV000369254	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000334553	SCV000369255	likely benign	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 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	RCV000397452	SCV000369256	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000942711	SCV001088643	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000942711	SCV001142890	uncertain significance	not provided	2018-09-28	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002244761	SCV002513517	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 (rs373737642) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002246115	SCV002513518	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 (rs373737642) in neonatal diabetes yet.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323504	SCV004028626	benign	not specified	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.3989-10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00042 in 251402 control chromosomes, predominantly at a frequency of 0.0034 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 163200 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Neonatal Diabetes Mellitus phenotype (2.1e-08), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.