ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.962C>T (p.Pro321Leu) (rs12720449)

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Total submissions: 11
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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 RCV000586616 SCV000695984 uncertain significance not provided 2016-04-04 criteria provided, single submitter clinical testing Variant summary: The c.1343C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Leu. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is not found in 118590 control chromosomes. This variant has been reported in one affected family member with prolonged QT interval and 4 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. In addition, one clinical laboratory and one database classified this variant as VUS and pathogenic, respectively. Taken together, this variant is classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586616 SCV001148159 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001104824 SCV001261717 uncertain significance Short QT syndrome 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Health, Inc RCV001190423 SCV001357908 uncertain significance Arrhythmia 2020-02-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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.
Invitae RCV001226314 SCV001398625 uncertain significance Long QT syndrome 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 448 of the KCNQ1 protein (p.Pro448Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs12720449, ExAC no frequency). This variant has been reported in the literature in a family with sudden unexplained death and prolonged QT interval, who also carried another KCNQ1 variant. In that family, this variant was reported not to segregate with disease (PMID: 23392653). ClinVar contains an entry for this variant (Variation ID: 67027). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
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.

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