Submissions for variant NM_000218.3(KCNQ1):c.217C>A (p.Pro73Thr)

gnomAD frequency: 0.00015  dbSNP: rs199472676

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001579481	SCV000234552	uncertain significance	not provided	2024-07-11	criteria provided, single submitter	clinical testing	Reported in association with LQTS (PMID: 15840476, 20851114, 23098067, 24606995, 26743238); Also reported in individuals who harbor an additional pathogenic variant that could explain their phenotype (PMID: 24667783, 29598884, 28588847); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24606995, 23098067, 19716085, 25351510, 22949429, 19862833, 19841300, 26633542, 20851114, 26986070, 28595573, 28588847, 28988457, 29197658, 29598884, 33181513, 31737537, 24667783, 15840476, 26743238, 22581653, 32048431, RidaM2023[Preprint], 37937776, 37449562)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415717	SCV000493748	uncertain significance	Short QT syndrome type 2	2015-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415657	SCV000493749	uncertain significance	Long QT syndrome 1	2015-10-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620808	SCV000737803	likely benign	Cardiovascular phenotype	2023-10-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000627157	SCV000748008	uncertain significance	Long QT syndrome	2017-06-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627157	SCV002222934	uncertain significance	Long QT syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the KCNQ1 protein (p.Pro73Thr). This variant is present in population databases (rs199472676, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 15840476, 19716085, 22949429, 24606995, 24667783, 26743238, 28588847). ClinVar contains an entry for this variant (Variation ID: 53031). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNQ1 protein function with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002477154	SCV002790816	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2022-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155056	SCV003844835	likely benign	not specified	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.217C>A (p.Pro73Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 150334 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Long QT Syndrome phenotype (8.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.217C>A has been reported in the literature in individuals affected with Long QT Syndrome (Example: Tester_2005, Kapa_2009, Kapplinger_2009, Marschall_2019, Millat_2011) etc . These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.87C>A, p.Phe29Leu; SCN5A c.1231G>A, p.Val411Met; KCNQ1 c.502G>A, P.Gly168Arg) (Mullertz_2018, Magnusson_2017, Riuro_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057655	SCV000089174	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579481	SCV001807424	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001579481	SCV001919338	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579481	SCV001932580	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579481	SCV001957178	uncertain significance	not provided		no assertion criteria provided	clinical testing