Submissions for variant NM_000352.6(ABCC8):c.-19A>G

gnomAD frequency: 0.01648  dbSNP: rs193922394

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000242519	SCV000051894	benign	not specified	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.-19A>G is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.002 in 134754 control chromosomes, predominantly at a frequency of 0.044 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2112000 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 African or African-American origin. To our knowledge, no occurrence of c.-19A>G in individuals affected with Neonatal Diabetes Mellitus and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000242519	SCV000303787	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000267816	SCV000369431	benign	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 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	RCV000325185	SCV000369432	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 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	RCV000382247	SCV000369433	likely benign	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 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.
GeneDx	RCV001668134	SCV001888286	benign	not provided	2018-11-10	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002254148	SCV002524155	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 ( rs193922394) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002254149	SCV002524156	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 ( rs193922394) in neonatal diabetes yet.