Submissions for variant NM_000352.6(ABCC8):c.4446C>A (p.Ser1482Arg)

dbSNP: rs1554904107

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666196	SCV000790448	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-03-21	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002245084	SCV002513302	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 (rs1554904107 ) in neonatal diabetes yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002245083	SCV002513303	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 (rs1554904107) in MODY yet.
Invitae	RCV003151131	SCV004295370	likely pathogenic	not provided	2023-04-14	criteria provided, single submitter	clinical testing	This variant is also known as c.4449C>A (p.Ser1483Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 12169627). 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 expected to disrupt ABCC8 protein function. ClinVar contains an entry for this variant (Variation ID: 551204). This missense change has been observed in individual(s) with congenital hyperinsulinism (PMID: 23345197). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1482 of the ABCC8 protein (p.Ser1482Arg).
Genetic Services Laboratory, University of Chicago	RCV003151131	SCV003839459	likely pathogenic	not provided	2022-09-02	no assertion criteria provided	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4446C>A, in exon 37 that results in an amino acid change, p.Ser1482Arg. This sequence change has previously been identified in the compound heterozygous state with a known pathogenic variant in an individual with congenital hyperinsulinism (PMID: 23345197). This sequence change has also not been described in population databases such as ExAC and gnomAD. The p.Ser1482Arg change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Ser1482Arg substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.