Submissions for variant NM_000218.3(KCNQ1):c.1014CTT[1] (p.Phe340del)

dbSNP: rs397508068

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045930	SCV000073943	pathogenic	Long QT syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This variant, c.1017_1019del, results in the deletion of 1 amino acid(s) of the KCNQ1 protein (p.Phe340del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397508068, gnomAD 0.003%). This variant has been observed in individuals with long QT syndrome (PMID: 9702906, 16922724, 24606995, 26669661). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52930). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000505797	SCV000234577	pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies suggest a damaging effect via reduced potassium channel function (Thomas et al., 2005); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 31447099, 9702906, 10973849, 19716085, 17470695, 16922724, 26669661, 15950200, 34505893, 24606995, 25294783)
Ambry Genetics	RCV000621148	SCV000738227	pathogenic	Cardiovascular phenotype	2021-09-09	criteria provided, single submitter	clinical testing	The c.1017_1019delCTT pathogenic mutation (also known as p.F340del) is located in coding exon 7 of the KCNQ1 gene. This pathogenic mutation results from an in-frame CTT deletion at nucleotide positions 1017 to 1019. This results in the in-frame deletion of a phenylalanine at codon 340. This alteration, also referred to as F339del, has been reported in multiple individuals with long QT syndrome (Ackerman MJ et al. Pediatr. Res., 1998 Aug;44:148-53; Splawski I et al. Circulation, 2000 Sep;102:1178-85; Thomas D et al. Cardiovasc. Res., 2005 Aug;67:487-97; Moss AJ et al. Circulation, 2007 May;115:2481-9; Christiansen M et al. BMC Med. Genet., 2014 Mar;15:31; Itoh H et al. Eur. J. Hum. Genet., 2016 Aug;24:1160-6). In addition, this alteration segregated with the disease in two apparently unrelated families (Ackerman MJ et al. Pediatr. Res., 1998 Aug;44:148-53; Thomas D et al. Cardiovasc. Res., 2005 Aug;67:487-97), and was suggested to attenuate channel activity (Thomas D et al. Cardiovasc. Res., 2005 Aug;67:487-97; Moss AJ et al. Circulation, 2007 May;115:2481-9). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000045930	SCV000987551	pathogenic	Long QT syndrome		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496698	SCV002783372	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-11-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000045930	SCV005426327	pathogenic	Long QT syndrome	2024-06-09	criteria provided, single submitter	clinical testing	This variant, also known as delF339 in literature, deletes one of the two consecutive phenylalanine residues in exon 7 of the KCNQ1 protein. This variant is found within the highly conserved transmembrane domain S6 (a.a. 328-348). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction of channel current amplitudes when expressed in Xenopus oocytes (PMID: 15950200). This variant has been reported in at least 8 unrelated individuals affected with long QT syndrome (PMID: 9702906, 15234419, 15950200, 17470695, 22456477, 25294783, 32893267). It has been shown that this variant segregates with disease in over 10 individuals from 4 of these families (PMID: 9702906, 15234419, 15950200, 25294783). This variant has been identified in 1/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.