Submissions for variant NM_000218.3(KCNQ1):c.958C>T (p.Pro320Ser)

dbSNP: rs199472753

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182143	SCV000234446	likely pathogenic	not provided	2021-11-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); At the protein level, silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 67130; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 22581653, 23392653, 19540844, 26669661, 29033053, 27041150, 32383558)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466144	SCV000543308	pathogenic	Long QT syndrome	2024-06-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the KCNQ1 protein (p.Pro320Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 23392653; Invitae). ClinVar contains an entry for this variant (Variation ID: 67130). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro320 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19540844, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182143	SCV001713553	likely pathogenic	not provided	2020-03-19	criteria provided, single submitter	clinical testing	PS4_Moderate, PM2, PM5, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000466144	SCV002598582	pathogenic	Long QT syndrome	2022-09-16	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.958C>T (p.Pro320Ser) 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 253994 control chromosomes. c.958C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002381371	SCV002694926	likely pathogenic	Cardiovascular phenotype	2019-06-05	criteria provided, single submitter	clinical testing	The p.P320S variant (also known as c.958C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 958. The proline at codon 320 is replaced by serine, an amino acid with similar properties, and is located in the pore domain. This variant was detected in an individual with prolonged QT, who also had an additional KCNQ1 variant detected, as well as in her affected son who had prolonged QT and only this variant (Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200). In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data, Sun J et al. Cell, 2017 Jun;169:1042-1050.e9). Alternate amino acid substitutions at this codon, p.P320A and p.P320H, have also been reported in LQTS cohorts, and functional studies supported a dominant negative impact for both variants (Donger C et al. Circulation, 1997 Nov;96:2778-81; Thomas D et al. J. Mol. Cell. Cardiol., 2010 Jan;48:230-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002468561	SCV002765086	likely pathogenic	Long QT syndrome 1	2022-11-29	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057827	SCV000089347	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223841	SCV000280168	uncertain significance	not specified		no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Pro320Ser Given the weak case data and minimal controls, we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in at least one unrelated cases of long QT syndrome (not including this patient's family), possibly two. There is weak segregation data. The variant was reported in one individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Ancestry was not provided. Ackerman's group later reported a patient seen in their Mayo LQTS clinic who was a compound heterozygote for this variant and p.Pro448Leu (Giudicessi et al 2013). The patient was a female with a QTc of 499 ms, one syncopal episode, and normal hearing. Several family members who carry just p.Pro448Leu had normal QTc measurements while the proband's son carried just p.Pro320Ser and had a QTc of 505 ms. Ancestry was not provided. That case may overlap with Kapplinger et al (2009) as some of the patients had commercial genetic testing. Unfortunately insufficient information is provided in Kapplinger et al (2009) to determine if it is in fact the same case. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 1.000). The proline at codon 320 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Pro320Ala, p.Pro320His) and nearby codons (p.Val310Asn, p.Val310Ile, p.Gly314Asn, p.Gly314Arg, p.Gly314Ser, p.Gly316Glu, p.Gly316Arg, p.Gly316Val, p.Gly316Val, p.Lys318Asn, p.Thr322Ala, p.Thr322Lys, p.Thr322Met, p.Gly325Arg, p.Gly325Glu, p.Gly325Trp). In total the variant has not been seen in ~9800 published controls and individuals from publicly available population datasets. There is no variation at codon 320 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 8th, 2014). The variant is listed in dbSNP (rs199472753), however the only submission is a locus specific database noting reports with disease in the literature. The variant was not observed in the following published control samples: 1300 ostensibly healthy individuals (Kapplinger et al 2009).