Submissions for variant NM_000218.3(KCNQ1):c.1343C>T (p.Pro448Leu)

dbSNP: rs12720449

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182185	SCV000234488	likely benign	not specified	2017-04-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182185	SCV000695984	uncertain significance	not specified	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1343C>T (p.Pro448Leu) 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 2e-05 in 250376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1343C>T has been reported in the literature in one affected family member with prolonged QT interval and four unaffected family members, but not in another family members with prolonged QT interval, indicating the variant of interest is not associated with the disease in this family (Kapplinger_2009, Giudicessi_2013). At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in mild effect on protein function (Glazer_2021) in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 23392653, 34930020, 19716085, 25854863, 29033053). ClinVar contains an entry for this variant (Variation ID: 67027). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000586616	SCV001148159	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104824	SCV001261717	uncertain significance	Short QT syndrome type 2	2019-05-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104825	SCV001261718	uncertain significance	Jervell and Lange-Nielsen syndrome 1	2019-05-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104826	SCV001261719	uncertain significance	Long QT syndrome 1	2019-05-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104827	SCV001261720	uncertain significance	Atrial fibrillation, familial, 3	2019-05-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001841663	SCV001357908	uncertain significance	Cardiac arrhythmia	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 448 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 results in reduced channel peak current density when expressed in Chinese hamster ovary cells (PMID: 34930020). This variant has been reported in a proband affected with long QT syndrome as well as in four relatives with normal QT intervals (PMID: 23392653). In this family, another four individuals with significant QT prolongation were not carriers of this variant, but a different variant in the same gene, p.Pro320Ser (ClinVar variation ID 67130), which was also carried by the proband. This variant has also been reported in another individual noted with syncope in a population screening study, who had no previous indication for cardiac genetic screening (PMID: 34930020). This variant has been identified in 7/281750 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182185	SCV001365672	likely benign	not specified	2020-03-04	criteria provided, single submitter	clinical testing	The p.Pro448Leu variant in KCNQ1 is classified as likely benign due to a lack of conservation across species as 4 mammals carry a leucine (Leu) at this position despite high nearby amino acid conservation. In addition, computational prediction tools predict that this variant does not impact the protein. This variant has been identified in 0.03% (2/7204) of "other population" chromosomes and 0.004% (5/128667) of European chromosomes (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BP4_Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226314	SCV001398625	likely benign	Long QT syndrome	2025-01-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001226314	SCV004836421	uncertain significance	Long QT syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 448 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 results in reduced channel peak current density when expressed in Chinese hamster ovary cells (PMID: 34930020). This variant has been reported in a proband affected with long QT syndrome as well as in four relatives with normal QT intervals (PMID: 23392653). In this family, another four individuals with significant QT prolongation were not carriers of this variant, but a different variant in the same gene, p.Pro320Ser (ClinVar variation ID 67130), which was also carried by the proband. This variant has also been reported in another individual noted with syncope in a population screening study, who had no previous indication for cardiac genetic screening (PMID: 34930020). This variant has been identified in 7/281750 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.
Ambry Genetics	RCV004017362	SCV004849040	uncertain significance	Cardiovascular phenotype	2019-10-02	criteria provided, single submitter	clinical testing	The c.1343C>T (p.P448L) alteration is located in exon 10 (coding exon 10) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 1343, causing the proline (P) at amino acid position 448 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057579	SCV000089098	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.