Submissions for variant NM_000525.4(KCNJ11):c.1040G>A (p.Arg347His)

gnomAD frequency: 0.00002  dbSNP: rs771797701

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668406	SCV000793000	uncertain significance	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2	2017-07-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712156	SCV000842581	uncertain significance	not provided	2017-09-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108706	SCV001265975	uncertain significance	Maturity-onset diabetes of the young type 13	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108707	SCV001265976	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174374	SCV001337512	uncertain significance	Monogenic diabetes	2018-03-02	criteria provided, single submitter	research	ACMG criteria: PP3 (9 predictors)=VUS
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227200	SCV002506476	uncertain significance	Maturity onset diabetes mellitus in young		criteria provided, single submitter	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 (rs771797701) in MODY yet.
Fulgent Genetics, Fulgent Genetics	RCV002477492	SCV002793850	uncertain significance	Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2; Type 2 diabetes mellitus; Maturity-onset diabetes of the young type 13; Diabetes mellitus, permanent neonatal 2	2022-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002532072	SCV003708972	uncertain significance	Inborn genetic diseases	2021-12-28	criteria provided, single submitter	clinical testing	The c.1040G>A (p.R347H) alteration is located in exon 1 (coding exon 1) of the KCNJ11 gene. This alteration results from a G to A substitution at nucleotide position 1040, causing the arginine (R) at amino acid position 347 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (6/251414) total alleles studied. The highest observed frequency was 0.01% (6/113716) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155266	SCV003844888	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: KCNJ11 c.1040G>A (p.Arg347His) results in a non-conservative amino acid change located in the inward rectifier potassium channel, C-terminal domain (IPR041647) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251414 control chromosomes, found exclusively within the Non-Finnish European subpopulation at a frequency of 5.3e-05 in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1040G>A has been reported in the literature as a VUS in settings of multigene testing in an individual affected with congenital hyperinsulinism and in an individual suspected of monogenic diabetes with a positive family history (Kapoor_2013, Donath_2019). These reports do not provide unequivocal conclusions about association of the variant with congenital hyperinsulinism or monogenic diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001275130	SCV001459961	uncertain significance	Permanent neonatal diabetes mellitus	2020-09-16	no assertion criteria provided	clinical testing