ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.517G>A (p.Ala173Thr) (rs120074187)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057789 SCV000234431 uncertain significance not provided 2018-07-15 criteria provided, single submitter clinical testing The A300T variant of uncertain significance in the KCNQ1 gene was previously reported in a9-year-old boy with LQTS who was homozygous for the variant, but did not have hearing losstypically seen in autosomal recessive JLNS (Priori et al., 1998). Both consanguineous parents of theproband were heterozyous for A300T and did not have features of LQTS (Priori et al., 1998).Subsequently, Burgos et al (2016) reported a Colombian individual with a very severe" LQTSphenotype who harbored A300T, in addition to SCN5A A467S and KCNQ1 A344V. A300T andSCN5A A467S were each inherited from an unaffected heterozygous parent, while the KCNQ1 A344Vvariant arose de novo (Burgos et al., 2016). The A300T variant was identified in trans with theKCNQ1 P535T variant via postmortem genetic testing in a 7 year-old child with history of syncope,normal hearing, and sudden unexplained death (Antúnez-Argüelles et al., 2017). Cascade familialtesting revealed the decedent's father and brother each harbored A300T; both were clinicallyasymptomatic with normal QTc intervals (Antúnez-Argüelles et al., 2017). Similarly, A300T has beenidentified in conjunction with additional cardiogenetic variants in multiple individuals (all of Hispanicancestry) referred for LQTS genetic testing at GeneDx. The A300T variant was observed in 9/33,568(0.03%) alleles from individuals of Latino ancestry in the gnomAD dataset (Lek et al., 2016).A300T, located within the intramembrane pore-forming helix between S5-S6 of the KCNQ1 protein,is a non-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size, and/or other properties. Moreover, this substitutionoccurs at a position that is conserved across species. Consequently, in silico analysis predicts thisvariant is probably damaging to the protein structure/function. Published functional studiesdemonstrated that the A300T variant reduces the Iks current, but does not show a dominant-negativeeffect (Priori et al., 1998; Bianchi et al., 2000). Furthermore, Bianchi et al (2000) reported that thepresence of a heterozygous A300T variant is associated with a mild cellular phenotype and mildclinical presentation.At this time, available information suggests that A300T may contribute to disease, but alone is notsufficient to cause disease when present in the heterozygous state."
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000003276 SCV000579480 likely pathogenic Long QT syndrome 1 2017-06-01 criteria provided, single submitter clinical testing
Invitae RCV000541920 SCV000627402 uncertain significance Long QT syndrome 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 300 of the KCNQ1 protein (p.Ala300Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs120074187, ExAC 0.03%). This variant has been observed to be heterozygous, homozygous, or in combination with another KCNQ1 variant in families affected with long QT syndrome or unexpected sudden death (PMID: 9641694, 28600177, 27251404, Invitae); however, this variant also has been reported to be heterozygous in unaffected relatives in these families. ClinVar contains an entry for this variant (Variation ID: 3128). Experimental studies have shown that this missense change is associated with a reduction of potassium ion channel current, but does not produce a dominant-negative effect, thus suggesting a modified impact on KCNQ1 function (PMID: 9641694, 11087258, 30571187). 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.
Ambry Genetics RCV000621158 SCV000737397 uncertain significance Cardiovascular phenotype 2016-10-04 criteria provided, single submitter clinical testing The p.A300T variant (also known as c.898G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 898. The alanine at codon 300 is replaced by threonine, an amino acid with similar properties. This variant has been reported in homozygous individuals with clinical diagnoses of long QT syndrome (LQTS) in the presence of normal hearing, thus atypical of autosomal recessive Jervell and Lange-Nielsen syndrome​ (JLNS). In these families, this variant has been detected in unaffected heterozygous relatives, suggesting an autosomal recessive cardiovascular phenotype or co-segregation with incomplete penetrance (Priori SG et al. Circulation, 1998 Jun;97:2420-5; Riuró H et al. Eur J Hum Genet. 2015 Jan;23:79-85). In another study, this variant was observed to occur in conjunction with a different de novo alteration in KCNQ1 and an alteration in SCN5A in an individual described by the authors to have a severe LQTS phenotype (Burgos M et al. Mol Diagn Ther. 2016;20:353-62). In functional in vitro analyses, this variant has been suggested to decrease sodium currents in a mock homozygous state, but does not result in dominant negative effects, consistent with an autosomal recessive inheritance pattern (Priori SG et al 1998; Bianchi L et al. Am J Physiol Heart Circ Physiol. 2000;279:H3003-11). This variant was previously reported in the SNPDatabase as rs120074187. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (4/104142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Limited data suggest this variant may have clinical impact when present in the homozygous state; however, the clinical impact of this variant in the heterozygous state remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000182128 SCV000740343 uncertain significance not specified 2016-06-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001102802 SCV001259492 benign Short QT syndrome 2 2017-09-11 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001102803 SCV001259493 uncertain significance Atrial fibrillation, familial, 3 2017-09-11 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 RCV000003276 SCV001259494 uncertain significance Long QT syndrome 1 2017-09-11 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 RCV001104722 SCV001261608 uncertain significance Jervell and Lange-Nielsen syndrome 1 2017-09-11 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 RCV001186217 SCV001352582 uncertain significance Arrhythmia 2020-11-04 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 300 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes a reduced cell current, a hyperpolarizing shift in activation, and a faster activation rate of the channel (PMID: 9641694, 11087258, 30571187). This variant has been reported in three unrelated individuals affected with long QT syndrome or sudden unexplained death, either in homozygous (PMID: 9641694) or compound heterozygous state (PMID: 27251404, 28600177). Heterozygous family members of these patients were reported to be normal. This variant has also been reported in other unrelated unaffected individuals (PMID: 19841300, 22949429). This variant has been identified in 12/249914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although studies suggests that this variant may be associated with autosomal recessive phenotype, the available evidence is insufficient to determine the role of this variant in autosomal dominant long QT syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM RCV000003276 SCV000023434 pathogenic Long QT syndrome 1 2003-05-08 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057789 SCV000089308 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:9641694;PMID:14678125;PMID:19841300;PMID:9927399;PMID:17999538).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182128 SCV000280166 uncertain significance not specified 2014-02-18 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.Ala300Thr Ala300Thr was previously reported in a 9-year-old boy with LQTS who was homozygous for the variant but did not exhibit the hearing loss typical of recessive Jervell and Lange-Nielsen syndrome (Priori et al. 1998). The boy’s parents were consanguineous, and they each carried a single copy of Ala300Thr but did not show features of LQTS. (Note: It is also present in PhenCode, which points to an entry in the Long QT Syndrome Database from a group in Denmark.) This is a non-conservative amino acid change, resulting in the replacement of an alanine (nonpolar) with a threonine (polar). Alanine at this location is highly conserved across mammalian species (conserved in 7 of 8 mammalian species). The adjacent residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.000. Functional studies by Bianchi et al. (2000) reportedly demonstrate that Ala300Thr reduces the potassium current of the channel but does not show a dominant negative effect. Priori et al. (1998) report that functional evaluation of mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate consistent with a mild mutation likely to require homozygosity to manifest the phenotype. Variants in nearby residues (Ala302Glu, Ala302Thr, Ala302Val, Leu303Pro) have been reported in association with LQTS, supporting the functional importance of this region of the protein. In total the variant has been seen in at least 1/7700 individuals from published controls and publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4000 Caucasian and ~2000 African American individuals (as of November 13, 2013). There is also no variation at this codon listed in 1000 genomes. This variant has been reported in dbSNP. The variant was also identified in 1 published control individual (of Asian descent) out of ~1700 tested: 0/100 tested by Priori et al., 1/1300 tested by Kapa et al.

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