ClinVar Genomic variation as it relates to human health

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, 33693037). This variant has been reported in an individual affected with sudden unexplained death (PMID: 28600177), in at least three unrelated individuals affected with long QT syndrome including one homozygous boy with normal hearing whose parents were consanguineous, both heterozygous for A300T and with normal QT interval and no symptoms, and one individual with severe phenotype who also carried another de novo pathogenic variant in the KCNQ1 gene (PMID: 9641694, 27251404, 32268277, 32893267), and in five asymptomatic family members (PMID: 9641694, 27251404, 28600177). This variant has also been reported in another two unrelated healthy individuals (PMID: 19841300, 22949429). This variant has been identified in 12/249914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Variant summary: KCNQ1 c.898G>A (p.Ala300Thr) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249914 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in KCNQ1 causing Jervell And Lange-Nielsen Syndrome (4.8e-05 vs 0.0024), allowing no conclusion about variant significance. c.898G>A has been reported in the literature in multiple biallelic individuals affected with earlier onset Romano-Ward type of LQTS2, sudden unexplained death, LQTS. However, heterozygous family members reported normal QT intervals (examples: Priori_ 1998, Antunez-Arguelles_ 2012, Burgos_ 2016). These data indicate that the variant may be associated with disease. Multiple reports have shown experimental evidence that this variant affects the normal protein function (Priori_ 1998, Bianchi_ 2000) and at-least one report showed it is consistent with a recessive trait (Gonzalez-Garrido_ 2021). The following publications have been ascertained in the context of this evaluation (PMID: 9641694, 11087258, 28600177, 33693037, 27251404). ClinVar contains an entry for this variant (Variation ID: 3128). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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.

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.

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.

Identified in patients with LQTS referred for genetic testing at GeneDx and in published literuture (Burgos et al., 2016; Scwartz et al., 2021); at least one patient harbored additional cardiogenetic variants; Identified in the homozygous state in a 9-year-old boy with LQTS but no history of hearing loss; both consanguineous parents of the proband were heterozyous for A300T and did not have features of LQTS (Priori et al., 1998); Published functional studies demonstrated that the A300T variant reduces the Iks current, but does not show a dominant-negative effect (Priori et al., 1998; Bianchi et al., 2000). Furthermore, Bianchi et al (2000) reported that the presence of a heterozygous A300T variant is associated with a mild cellular phenotype and mild clinical presentation; 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: 17999538, 19841300, 23591039, 19862833, 9927399, 14678125, 22949429, 12205113, 11530094, 27041150, 29021305, 29033053, 29197658, 30571187, 9641694, 33693037, 34505893, 11087258, 27251404, 28600177)

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, 33693037). This variant has been reported in individuals affected with sudden unexplained death (PMID: 28600177), Jervell and Lange-Nielsen syndrome (PMID: 34165182), or long QT syndrome (PMID: 9641694, 27251404, 32268277, 32893267). One of these individuals also carried another de novo pathogenic variant in the KCNQ1 gene (PMID: 27251404). This variant has also been observed in asymptomatic family members (PMID: 9641694, 27251404, 28600177) and healthy individuals (PMID: 19841300, 22949429). This variant has been identified in 12/249914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 300 of the KCNQ1 protein (p.Ala300Thr). This variant is present in population databases (rs120074187, gnomAD 0.03%). This missense change has been observed in individuals with autosomal dominant long QT syndrome and/or autosomal recessive long QT syndrome or unexpected sudden death without hearing loss typically associated with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 9641694, 27251404, 28600177, 34505893; Invitae). ClinVar contains an entry for this variant (Variation ID: 3128). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9641694, 11087258, 30571187, 33693037). This variant disrupts the p.Ala300 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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, and is located in the pore region. 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 as having severe LQTS phenotype (Burgos M et al. Mol Diagn Ther. 2016;20:353-62). This variant was also detected in the compound heterozygous state with a second KCNQ1 variant in a sudden death case where heterozygous relatives with p.A300T only were unaffected (Antúnez-Argüelles E et al. Gene. 2017 Sep;627:40-48). In functional in vitro analyses, this variant resulted in decreased channel currents, but did 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; González-Garrido A et al. Front Cardiovasc Med. 2021 Feb;8:625449). 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 available evidence, this variant may have clinical impact when present in the homozygous or compound heterozygous state; however, autosomal recessive inheritance of KCNQ1-related LQTS without hearing loss is not well-established, and the clinical impact of this variant in the heterozygous state remains unclear.

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.

This variant has been reported in the following publications (PMID:9641694;PMID:14678125;PMID:19841300;PMID:9927399;PMID:17999538).