Submissions for variant NM_000218.3(KCNQ1):c.899C>A (p.Ala300Glu)

dbSNP: rs1001293702

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470657	SCV000543300	pathogenic	Long QT syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 300 of the KCNQ1 protein (p.Ala300Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 405257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. This variant disrupts the p.Ala300 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 9641694, 11087258, 27251404, 28600177, 30571187, 33693037; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001558264	SCV001780174	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature (PMID: 34505893); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34505893)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224284	SCV003920105	uncertain significance	Atrial fibrillation, familial, 3; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-03-30	criteria provided, single submitter	clinical testing	KCNQ1 NM_000218.2 exon 6 p.Ala300Glu (c.899C>A): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:405257). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV000470657	SCV004842601	uncertain significance	Long QT syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701492	SCV005202794	uncertain significance	not specified	2024-07-25	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.899C>A (p.Ala300Glu) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.899C>A has been reported in the literature in individuals suspected of long QT syndrome type 1 (example: Schwartz_2021) . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34505893). ClinVar contains an entry for this variant (Variation ID: 405257). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.