Submissions for variant NM_000218.3(KCNQ1):c.932C>T (p.Thr311Ile)

dbSNP: rs199472746

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513653	SCV003439768	uncertain significance	Long QT syndrome	2022-04-15	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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15498462, 20368164, 25705178). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 53134). This variant is also known as KVLQT1 p.T182I. This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 9482580, 14678125). This variant is present in population databases (rs199472746, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 311 of the KCNQ1 protein (p.Thr311Ile).
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV003319314	SCV004024203	likely pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003319314	SCV005399461	likely pathogenic	Long QT syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional ion transporter domain (pore) (DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes (p.(Thr311Ala, p.(Thr311Leu)) have been reported in at least two individuals with long QT syndrome (LQTS) (LOVD, PMID: 20541041, PMID: 15733182). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been observed in at least two unrelated individuals with LQTS (LOVD, PMID: 9482580, PMID: 10973849, PMID: 14678125). (SP) 0903 - This variant has limited evidence for segregation with disease, where it was found in three affected relatives with LQTS (PMID: 9482580). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Whole cell patch clamp studies of transfected CHO cells have demonstrated impaired current. However, the biological significance of this study is uncertain (PMID: 25705178). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057807	SCV000089327	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:9482580;PMID:14678125). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.