ClinVar Genomic variation as it relates to human health

PP1_strong, PP3, PM1, PM2, PS3_supporting, PS4

Identified in numerous patients with LQTS referred for genetic testing at GeneDx and in published literature; reported to be generally severe in clinical expression with patients demonstrating more frequent cardiac events beginning at younger ages compared to the overall LQTS population (PMID: 8528244, 10376919, 12402336, 16246960, 17984373, 22949429, 26118460, 29194874); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a disruption of the normal electrophysiological properties and a non-functional channel (PMID: 15051636, 21854832, 22095730, 24705789, 34505893); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9570196, 29740400, 21810471, 25634836, 10376919, 24705789, 21854832, 24912595, 15051636, 12402336, 22949429, 17984373, 26910742, 26118460, 28003625, 8528244, 29194874, 18308161, 14678125, 16627448, 19841300, 8872472, 8818942, 17470695, 9386136, 16155735, 16922724, 15840476, 15234419, 19716085, 10973849, 29439887, 30898243, 30878014, 31737537, 30847666, 32443288, 36243179, 34546463, 34505893, 32383558, 32470535, 34860437, 16246960, 22095730)

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.

The c.1022C>T (p.Ala341Val) missense variant in KCNQ1 gene has been reported in individuals affected with long QT syndrome (Brink et al., 2005). This variant has been observed to segregate with long QT syndrome (LQTS) in several families (Brink et al., 2005). Experimental studies have shown that this missense change reduces the current of the KCNQ1 channel in a dominant negative fashion (Brink et al., 2005). This variant disrupts the p.Ala341 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in affected individuals (Anastasakis et al., 2006), suggesting that it is a clinically significant residue. The p.Ala341Val variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ala at position 341 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala341Val in KCNQ1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

The p.A341V pathogenic mutation (also known as c.1022C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1022. The alanine at codon 341 is replaced by valine, an amino acid with similar properties. This alteration (historically described as A212V) has been reported as de novo in a family with monozygotic twins with long QT syndrome (LQTS) (Russell MW et al. Hum. Mol. Genet., 1996 Sep;5:1319-24). In addition, this variant has been reported in numerous individuals and families with LQTS, including reports as a founder mutation associated with severe phenotype in a large South African cohort (Anastasakis A et al. Europace, 2006 Apr;8:241-4; Crotti L et al. Circulation, 2007 Nov;116:2366-75; Wang Q et al. Nat. Genet., 1996 Jan;12:17-23). Additional alterations at this CpG dinucleotide position and in nearby amino acids have also been reported association with LQTS, leading researchers to consider this as a hot spot region (Wang Q et al. Nat. Genet., 1996 Jan;12:17-23; Russell MW et al. Hum. Mol. Genet., 1996 Sep;5:1319-24; Crotti L et al. Circulation, 2007 Nov;116:2366-75). Functional studies demonstrated a defective protein producing little or no activating potassium channel current, thereby causing a pronounced prolongation of repolarization (Mikuni I et al. Biochim. Biophys. Acta, 2011 Dec;1810:1285-93; Heijman J et al. Circ. Res., 2012 Jan;110:211-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated S6 transmembrane domain (PMID: 19716085). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. An alternative change to a glutamic acid and a glycine have been reported in multiple individuals with LQTS (ClinVar, PMID: 19716085). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a South African founder mutation and has multiple pathogenic entries in ClinVar (PMID: 24217263, 19716085). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the KCNQ1 protein (p.Ala341Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 16246960, 16627448). It is commonly reported in individuals of South African ancestry (PMID: 8528244, 15051636, 16246960, 16627448, 17984373, 22949429, 25634836). ClinVar contains an entry for this variant (Variation ID: 3121). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (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 determined to be pathogenic (PMID: 8528244, 10086971, 16627448). 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.

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.

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.

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).