Submissions for variant NM_000352.6(ABCC8):c.4615G>A (p.Val1539Met)

dbSNP: rs193922408

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234921	SCV000051916	uncertain significance	not specified	2023-05-04	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.4615G>A (p.Val1539Met) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250682 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4615G>A has been reported in the literature in an individual affected with late onset diabetes/hyperinsulinism (de Franco_2020). This report does not provide unequivocal conclusions about association of the variant with Neonatal Diabetes Mellitus. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32027066). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as VUS (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001762057	SCV001990207	uncertain significance	not provided	2019-07-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001762057	SCV002128694	uncertain significance	not provided	2022-02-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1539 of the ABCC8 protein (p.Val1539Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neonatal diabetes mellitus (PMID: 32027066). This variant is also known as c.4618G>A, p.(Val1540Met). ClinVar contains an entry for this variant (Variation ID: 35623). 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. 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002243674	SCV002512149	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 (rs193922408 ) in neonatal diabetes yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002243673	SCV002512150	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 (rs193922408 ) in MODY yet.
Genetic Services Laboratory, University of Chicago	RCV000501531	SCV000592975	likely pathogenic	Permanent neonatal diabetes mellitus	2017-04-04	flagged submission	clinical testing
Counsyl	RCV000984138	SCV001132109	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-09-19	no assertion criteria provided	clinical testing