Submissions for variant NM_000352.6(ABCC8):c.1970G>A (p.Arg657Gln)

gnomAD frequency: 0.00002  dbSNP: rs755707550

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668087	SCV000792634	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-07-05	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002267004	SCV002522294	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 (rs755707550) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002267005	SCV002522298	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 (rs755707550) in neonatal diabetes yet.
New York Genome Center	RCV002467983	SCV002764310	uncertain significance	Type 2 diabetes mellitus	2021-07-29	criteria provided, single submitter	clinical testing	The heterozygous c.1970G>A (p.Arg657Gln) missense variant identified in the ABCC8 gene has been reported as heterozygous in an individual affected with congenital hyperinsulinism of infancy [PMID: 26431509]. In vitro functional analysis was suggestive of a residual activation by diazoxide incorrespondence to the patient’s phenotype [41% decrease in activity; PMID: 26431509]. The variant has 0.00002628 allele frequency in the gnomAD(v3) database (4out of 152194 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant hasbeen reported in the ClinVar database as variant of uncertain significance [Variation ID:552764]. The variant affects a weakly conserved residue. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 16.81, REVEL score = 0.154). Due to the lack of compelling evidence for its pathogenicity, the heterozygous c.1970G>A (p.Arg657Gln) missense variant identified in the ABCC8 gene is reported as a Variant of UncertainSignificance.
Fulgent Genetics, Fulgent Genetics	RCV002485544	SCV002779364	uncertain significance	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2022-05-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509497	SCV002819772	uncertain significance	not specified	2022-12-04	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1970G>A (p.Arg657Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251014 control chromosomes. c.1970G>A has been reported in the literature as a heterozygous maternally inherited genotype in at-least one individual affected with Congenital hyperinsulinism of infancy (CHI) (example, Rozenkova_2015). It is not specified whether this individual had a diffuse or a focal lesion and a second paternally in inherited variant supporting a diffuse outcome is also not reported. Furthermore, the maternal inheritance of this variant rules out the possibility of a focal histology. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. At least one publication reports experimental evidence evaluating an impact on protein function (Rozenkova_2015). The most pronounced variant effect results in approximately 41% decrease in function of mutant K-ATP channels in-vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV002530735	SCV003440252	uncertain significance	not provided	2022-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 657 of the ABCC8 protein (p.Arg657Gln). This variant is present in population databases (rs755707550, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism (PMID: 26431509). ClinVar contains an entry for this variant (Variation ID: 552764). 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 not expected to disrupt ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 26431509). 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.