ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs771797701
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Total submissions: 10
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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

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