Submissions for variant NM_000525.4(KCNJ11):c.560C>T (p.Ala187Val)

gnomAD frequency: 0.00001  dbSNP: rs1371185696

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666176	SCV000790423	likely pathogenic	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2	2017-03-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868211	SCV002280896	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 187 of the KCNJ11 protein (p.Ala187Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive congenital hyperinsulinism and/or focal congenital hyperinsulinism (PMID: 11395395, 21422196, 21812132). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551187). 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 KCNJ11 protein function. This variant disrupts the p.Ala187 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ11-related conditions (PMID: 21422196, 23652837), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005407859	SCV006070731	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Variant summary: KCNJ11 c.560C>T (p.Ala187Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247860 control chromosomes. c.560C>T has been reported in the literature in individuals affected with Congenital Hyperinsulinism (Fournet_2001, Park_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11395395, 21422196). ClinVar contains an entry for this variant (Variation ID: 551187). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227197	SCV002506470	uncertain significance	Maturity onset diabetes mellitus in young		flagged submission	research	Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. It is also associated with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of this particular variant (rs1371185696) in MODY yet.