Submissions for variant NM_000891.3(KCNJ2):c.1244C>T (p.Pro415Leu)

gnomAD frequency: 0.00013  dbSNP: rs373799322

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757418	SCV000223555	uncertain significance	not provided	2024-11-08	criteria provided, single submitter	clinical testing	Identified as a variant of uncertain significance in an individual with arrhythmia (PMID: 23644778); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Kanika2016, 23644778)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757418	SCV000885630	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing	The p.Pro415Leu variant (rs373799322) has been previously identified in a single individual in a cohort of patients with long-QT syndrome (Limberg 2013); however, inheritance and specific clinical information were not reported for this individual. The p.Pro415Leu variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.014% in non-Finnish Europeans (identified in 18 out of 126,430 chromosomes) and is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 190819). The proline at codon 415 is highly conserved considering 14 species up to frog (Alamut software v2.9). Computational analyses predict conflicting effects of the p.Pro415Leu variant on KCNJ2 protein structure/function (SIFT: damaging, PolyPhen2: benign, MutationTaster: disease causing). Therefore, based on the available information, the clinical significance of the p.Pro415Leu variant cannot be determined with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067159	SCV001232202	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 415 of the KCNJ2 protein (p.Pro415Leu). This variant is present in population databases (rs373799322, gnomAD 0.01%). This missense change has been observed in individual(s) with premature ventricular complexes and ventricular tachycardia (PMID: 23644778). ClinVar contains an entry for this variant (Variation ID: 190819). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000757418	SCV002063656	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390406	SCV002668591	benign	Cardiovascular phenotype	2023-01-20	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002505232	SCV002814444	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3; Atrial fibrillation, familial, 9	2021-08-12	criteria provided, single submitter	clinical testing