ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.641C>T (p.Ala214Val) (rs12720459)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000171124 SCV000073946 pathogenic Long QT syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 341 of the KCNQ1 protein (p.Ala341Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome (LQTS) in several families (PMID: 16246960, 16627448). This variant has been reported as the most common cause of LQTS in the South African population, although it has also been described in many other ethnicities (PMID: 8528244, 16246960, 17984373, 25634836, 22949429, 15051636). ClinVar contains an entry for this variant (Variation ID: 3121). Experimental studies have shown that this missense change reduces the current of the KCNQ1 channel in a dominant negative fashion (PMID: 10376919, 16246960, 21854832, 22095730). This variant disrupts the p.Ala341 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 8528244, 10086971, 16627448), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000057528 SCV000234458 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The A341V pathogenic variant in the KCNQ1 gene is well described in association with LQTS and is generally severe in clinical expression demonstrating more frequent cardiac events starting at younger ages compared to the overall LQTS population (Wang et al., 1996; Wang et al., 1999; Jongbloed et al., 2002; Crotti et al., 2007; Giudicessi et al., 2012). Variants in the same residue (A341E) and in nearby residues (A344V and G345R) have been classified as likely pathogenic or pathogenic by GeneDx as well as reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Functional studies have shown that A341V disrupts the normal electrophysiological properties of the slowly activating delayed-rectifier potassium channel in a dominant negative manner and results in a non-functional channel (Westenskow et al., 2004; Mikuni et al., 2011; Heijman et al., 2012). Furthermore, the A341V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Ambry Genetics RCV000619686 SCV000737854 pathogenic Cardiovascular phenotype 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000003269 SCV000805151 pathogenic Long QT syndrome 1 2018-03-08 criteria provided, single submitter clinical testing
OMIM RCV000003269 SCV000023427 pathogenic Long QT syndrome 1 2005-10-25 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057528 SCV000089047 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:8528244;PMID:8818942;PMID:8872472;PMID:9386136;PMID:9570196;PMID:10973849;PMID:12402336;PMID:14678125;PMID:15028050;PMID:15051636;PMID:15840476;PMID:16155735;PMID:16922724;PMID:19716085;PMID:19841300;PMID:21810471;PMID:10376919;PMID:21854832;PMID:15234419;PMID:16246960;PMID:18308161;PMID:17470695;PMID:22095730).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000171124 SCV000223689 pathogenic Long QT syndrome 2014-12-02 no assertion criteria provided clinical testing Observed in one patient in Stanford Center for Inherited Cardiovascular Disease with long QT syndrome. Patient underwent genetic testing at GeneDx, which included sequencing and exon-level array analysis of AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, SCN5A, SCN4B, SNTA1. Given the very strong case and segregation data and absence in general population samples, we consider this variant very likely disease causing. This variant has been reported in at least 27 unrelated cases with Long QT syndrome (not including our patient). Wang et al (1996) initially reported 5 families with the p.Ala341Val variant and long QT Syndrome (reported as p.Ala212Val). The variant segregated with disease in 55 affected individuals across the 5 families (Family 1- 6 affected, Family 2- 18 affected, Family 3-18 affected, Family 4- 3 affected and Family 5-2 affected). These families were recruited from North America and Europe. Russell et al (1996) reported monozygotic twins with the variant and LQT. The variant was de novo; neither parent carried it, both parents had normal QT intervals, and paternity was confirmed by molecular analysis. The family for this study was recruited from Michigan and Atlanta. De Jager et al (1996) reported a family of Northern European Afrikaner descent with p.Ala341Val; in this family all the affected individuals shared a common disease associated haplotype thus indicating a founder effect in the South African population. Donger et al (1997) reported a family with 5 affected individuals- 2 had syncope before age 10 and 3 had a SCD before age 40. Li et al (1998) reported p.Ala341Val in 2 out of 115 families from the Int LQT Registry (N. America, Europe , Asia). One of these families can be viewed as additive since they are of Japanese origin and the prior studies only included European and American families. Splawski et al (2000) also reported 7 families with disease and variant but these were previously published cases (Wang, Russell, Donger and Li). Jongbloed et al (2002) identified the variant in 1 out of 32 families of Dutch and Belgian ancestry. Kobori et al (2004) reported 2 families with the variant. Westenskow et al (2004) reported a case with the p.Ala341Val variant in KCNQ1 and an additional variant in KCNE1 (p.P127T). The patients QTc was 530 ms. Tester et al (2005) reported 3 unrelated individuals with the variant out of 541 cases sent for genetic testing in Ackerman’s lab between August 1997 and July 2004. In 2005 Lai et al reported of a case positive for the variant who presented with an “attack” during swimming. Millat et al (2006) reported 2 unrelated cases with the variant: a 9 yo old male (QTc 503ms) with syncope triggered by swimming and a 16yo female (QTc 544 ms) with syncope and torsade de pointes. The variant was reported in 8 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). This may include our patient, given the timing. 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). In 2010, Kotta et al reported the variant in 1 out of 17 unrelated cases with LQT in Greece. This is a semi conservative amino acid change with a nonpolar, neutral Alanine replaced with a non polar neutral Valine. The variant is located in the S6 transmembrane domain of the K+ channel. In silico analysis (SIFT, PolyPhen) predicts the amino acid change to be deleterious to the resulting protein. Missense variants in the same codon and nearby codons (A341E, A341G, L342F, P343L, A344V) have been reported in association with LQTS. The variant is listed in genomemed.org, fsm, and hearing.harvard databases. There are no studies involving mouse models. In total, the variant has not been seen in ~8380 published controls, laboratory controls, and individuals from publicly available datasets not selected for Mendelian cardiovascular disease. Wang et al (1996) reported that the variant was absent in 200 presumably healthy controls of unspecified ancestry. Russell et al (1996) reported that the variant was not identified in 180 presumably healthy controls. Li et al (1998) report the variant was absent in 150 presumably healthy controls. Jonbloed et al (2002) indicate that p.Ala341Val was absent in 50 presumably healthy controls. Kapplinger et al (2009) report that p.Ala341Val was not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Thus in total the variant was absent in 1880 presumably healthy controls. The variant is listed in dbSNP with the rs # 12720459; however there is no allele frequency data available. There is no variation at codon 341 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of January 13th 2014). There is no non-synonymous variation at codon 341 listed in the Exome Aggregation Consortium dataset, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 1st, 2014). Note this includes the NHLBI ESP data reviewed above.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000057528 SCV000280134 pathogenic not provided 2015-06-05 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.Ala341Val Given the very strong case and segregation data and absence in general populations samples, we consider this variant very likely disease causing. This variant has been reported in at least 27 unrelated cases with Long QT Syndrome. Wang et al (1996) initially reported 5 families with the p.Ala341Val variant and long QT Syndrome (reported as p.Ala212Val). The variant segregated with disease in 55 affected individuals across the 5 families (Family 1- 6 affected, Family 2- 18 affected, Family 3-18 affected, Family 4- 3 affected and Family 5-2 affected). These families were recruited from North America and Europe. Russell et al (1996) reported monozygotic twins with the variant and LQT. The variant was de novo; neither parent carried it, both parents had normal QT intervals, and paternity was confirmed by molecular analysis. The family for this study was recruited from Michigan and Atlanta. De Jager et al (1996) reported a family of Northern European Afrikaner descent with p.Ala341Val; in this family all the affected individuals shared a common disease associated haplotype thus indicating a founder effect in the South African population. Donger et al (1997) reported a family with 5 affected individuals- 2 had syncope before age 10 and 3 had a SCD before age 40. Li et al (1998) reported p.Ala341Val in 2 out of 115 families from the Int LQT Registry (N. America, Europe , Asia). One of these families can be viewed as additive since they are of Japanese origin and the prior studies only included European and American families. Splawski et al (2000) also reported 7 families with disease and variant but these were previously published cases (Wang, Russell, Donger and Li). Jongbloed et al (2002) identified the variant in 1 out of 32 families of Dutch and Belgian ancestry. Kobori et al (2004) reported 2 families with the variant. Westenskow et al (2004) reported a case with the p.Ala341Val variant in KCNQ1 and an additional variant in KCNE1 (p.P127T). The patients QTc was 530 ms. Tester et al (2005) reported 3 unrelated individuals with the variant out of 541 cases sent for genetic testing in Ackerman’s lab between August 1997 and July 2004. In 2005 Lai et al reported of a case positive for the variant who presented with an “attack” during swimming. Millat et al (2006) reported 2 unrelated cases with the variant: a 9 yo old male (QTc 503ms) with syncope triggered by swimming and a 16yo female (QTc 544 ms) with syncope and torsade de pointes. The variant was reported in 8 individuals 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). In 2010, Kotta et al reported the variant in 1 out of 17 unrelated cases with LQT in Greece. This is a semi conservative amino acid change with a nonpolar, neutral Alanine replaced with a non polar neutral Valine. The variant is located in the S6 transmembrane domain of the K+ channel. In silico analysis (SIFT, PolyPhen) predicts the amino acid change to be deleterious to the resulting protein. Missense variants in the same codon and nearby codons (A341E, A341G, L342F, P343L, A344V) have been reported in association with LQTS. The variant is listed in genomemed.org, fsm, and hearing.harvard databases. There are no studies involving mouse models. In total, the variant has not been seen in ~8380 published controls, laboratory controls, and individuals from publicly available datasets not selected for Mendelian cardiovascular disease. Wang et al (1996) reported that the variant was absent in 200 presumably healthy controls of unspecified ancestry. Russell et al (1996) reported that the variant was not identified in 180 presumably healthy controls. Li et al (1998) report the variant was absent in 150 presumably healthy controls. Jonbloed et al (2002) indicate that p.Ala341Val was absent in 50 presumably healthy controls. Kapplinger et al (2009) report that p.Ala341Val was not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Thus in total the variant was absent in 1880 presumably healthy controls. The variant is listed in dbSNP with the rs # 12720459; however there is no allele frequency data available. There is no variation at codon 341 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of January 13th 2014). There is no non-synonymous variation at codon 341 listed in the Exome Aggregation Consortium dataset, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 1st, 2014). Note this includes the NHLBI ESP data reviewed above.

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