Submissions for variant NM_000218.3(KCNQ1):c.1355G>T (p.Arg452Leu)

dbSNP: rs145229963

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182318	SCV000234621	pathogenic	not provided	2012-01-09	criteria provided, single submitter	clinical testing	This missense change is denoted Arg452Leu (aka R452L) at the protein level and c.1355 G>T at the cDNA level. The Arg452Leu mutation has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Another mutation at this codon (Arg452Trp) has been published as a disease-causing mutation in one individual with LQTS and it was absent from 1,500 reference alleles ( Tester D et al., 2005). Arg452Leu results in a non-conservative amino acid substitution of a positively charged Arginine residue with a non-polar Leucine residue. Other mutations in nearby codons (Arg451Gln, Arg451Trp, His455Tyr) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Additionally, the NHLBI ESP Exome Variant Server reports Arg452Leu was not observed in approximately 5,300 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852308	SCV002303884	uncertain significance	Long QT syndrome	2020-11-11	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200904). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 452 of the KCNQ1 protein (p.Arg452Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine.
Ambry Genetics	RCV002381590	SCV002691764	uncertain significance	Cardiovascular phenotype	2020-10-26	criteria provided, single submitter	clinical testing	The p.R452L variant (also known as c.1355G>T), located in coding exon 10 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 1355. The arginine at codon 452 is replaced by leucine, an amino acid with dissimilar properties, and is located in the cytoplasmic C-terminal region. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001852308	SCV004836428	uncertain significance	Long QT syndrome	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes a reduction of channel current in transfected HEK293 cells (PMID: 34930020). This variant has been reported in an individual affected with premature ventricular contraction (PMID: 34930020). This variant has been identified in 2/249712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.