Submissions for variant NM_000891.3(KCNJ2):c.118C>T (p.Arg40Ter)

dbSNP: rs786205811

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170970	SCV000223533	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Reported in a 15-year-old female with characteristic physical features, PVCs, and bidirectional tachycardia consistent with Andersen-Tawil syndrome; this variant was present in four other individuals with only cardiac features of Andersen-Tawil syndrome (PMID: 22589293); Nonsense variant predicted to result in protein truncation as the last 388 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22589293, 33205612)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765066	SCV004571406	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg40*) in the KCNJ2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 388 amino acid(s) of the KCNJ2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Andersen-Tawil syndrome (PMID: 22589293, 33205612). ClinVar contains an entry for this variant (Variation ID: 190806). This variant disrupts a region of the KCNJ2 protein in which other variant(s) (p.Ser369*) have been determined to be pathogenic (PMID: 21493816). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004020038	SCV005036829	uncertain significance	Cardiovascular phenotype	2023-12-22	criteria provided, single submitter	clinical testing	The p.R40* variant (also known as c.118C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 118. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration has been reported in a subject with features of Anderson-Tawill syndrome (ATS) (Kimura H et al. Circ Cardiovasc Genet, 2012 Jun;5:344-53). This variant was also reported in a pregnant subject with features ATS and her mother with arrhythmia and her two siblings, though limited clinical information was available for family members (Inagaki M et al. J Obstet Gynaecol Res, 2021 Jan;47:446-451). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of KCNJ2 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.