Submissions for variant NM_000352.6(ABCC8):c.2500C>T (p.Arg834Cys)

gnomAD frequency: 0.00004  dbSNP: rs140068774

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000303371	SCV000369320	likely benign	Hyperinsulinemic hypoglycemia, familial, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000339611	SCV000369321	likely benign	Permanent neonatal diabetes mellitus	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000396695	SCV000369322	likely benign	Diabetes mellitus, transient neonatal, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002244774	SCV002515437	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 ( rs140068774) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002244775	SCV002515438	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 ( rs140068774) in neonatal diabetes yet.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002520701	SCV003440272	uncertain significance	not provided	2022-05-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 834 of the ABCC8 protein (p.Arg834Cys). This variant is present in population databases (rs140068774, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of ABCC8-related conditions (PMID: 9519757). ClinVar contains an entry for this variant (Variation ID: 303772). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9519757). 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.
Department of Traditional Chinese Medicine, Fujian Provincial Hospital	RCV002244774	SCV004934091	pathogenic	Maturity onset diabetes mellitus in young		no assertion criteria provided	research	We found that a 21-year-old female patient in China had the clinical phenotype of maturity-onset diabetes of the young, her fasting blood glucose could reach 30mmol/L, and she had severe acute complications such as ketoacidosis. Genetic testing indicated that the patient had a mutation in the ABCC8 gene (NM: 000352): C.2500c > T (P.arg834cys), and the mutation came from the patient's mother. The mutation is pathogenic according to ACMG score. Yasuharu et al. previously reported the related mutation (PMID:9519757). They found that the 835th amino acid on the same exon of the ABCC8 gene was mutated, and the amino acid mutated in this patient was the 834th. Therefore, the mutation of this patient may be consistent with their pathogenicity. Therefore, we believe that the new missense mutation in this patient is pathogenic.