ClinVar Miner

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

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Total submissions: 8
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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 2018-08-21 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 reported as homozygous in an individual affected with long QT syndrome and heterozygous in the individual’s unaffected parents (PMID: 9641694). It has been observed on the opposite chromosome (in trans) from another variant in KCNQ1 in an unexpected sudden death, and heterozygous in the individual’s unaffected father and sibling (PMID: 28600177). This variant has been reported in combination with a de novo pathogenic variant in KCNQ1 and another variant in SCN5A in an individual with long QT syndrome, while this variant was reported heterozygous in the unaffected father (PMID: 27251404). It has also been observed in another unrelated unaffected individual (PMID: 22949429). 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). 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 Lines of evidence used in support of classification: Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,2 of classification of c (below) met (2c = 1b),Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
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
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 ( 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 (, 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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