ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1013-1G>T (rs775537394)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182190 SCV000234493 pathogenic not provided 2018-05-11 criteria provided, single submitter clinical testing The c.1394-1 G>T pathogenic variant in KCNQ1 has been reported in one patient diagnosed with LQTS, who also had another frameshift variant in the KCNH2 gene, and was noted to have severe LQTS consistent with two pathogenic variants (Chung et al., 2007). The c.1394-1 G>T variant has also been observed in other unrelated individuals with LQTS, who were referred for genetic testing at GeneDx. Other splice site variants in the KCNQ1 gene have been reported in association with LQTS (Stenson et al., 2014). The variant destroys the canonical splice acceptor site in intron 10 and is expected to cause abnormal gene splicing. This may lead to loss of protein function due to protein truncation or absence of protein from this allele due to mRNA decay. Furthermore, the c.1394-1 G>T variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000620890 SCV000738035 pathogenic Cardiovascular phenotype 2017-05-25 criteria provided, single submitter clinical testing The c.1394-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 11 of the KCNQ1 gene. This alteration was reported as IVS10-1G>T in a subject with long QT syndrome (LQTS) who also carried a second frameshift alteration in KCNH2 (Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14). This alteration was also reported in an LQTS cohort; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000631611 SCV000752693 likely pathogenic Long QT syndrome 2019-09-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the KCNQ1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs775537394, ExAC 0.002%). This variant has been observed in individuals affected with long QT syndrome (PMID: 17905336, 26318259, Invitae) and referred for long QT syndrome testing (PMID: 23631430). This variant is also known as IVS10-1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 200847). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000631611 SCV000919557 pathogenic Long QT syndrome 2017-09-01 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.1394-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was found in the control population dataset of ExAC in 1/121208 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). This variant was reported in multiple patients with LQTS in the literature (Chung_2007, Lieve_2013, Ruwald_2016) and was stated as segregating with LQTS in a family (Stanford Center for Inherited Cardiovascular Disease). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182190 SCV000280145 likely pathogenic not provided 2013-10-31 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 IVS10-1G>T (c.1394-1G>T) Based on the data reviewed below, we consider it likely disease-causing. This variant has been seen in at least one published case in the literature. We have also found it segregating with LQTS in one family at our center. Chung et al. 2007 identified this splice variant in addition to a frameshift insertion in KCNH2 in a patient with “severe LQTS”. In terms of clinical details, this patient was Caucasian, had a personal history of syncope and a family history of SCD in a first degree relative, and had a QTc of 520 ms. Her diagnosis was described as “LQT1/LQT2”). It was absent from 50 control individuals in this study. This variant is very likely to disrupt normal splicing, as it changes the last base of intron 10 from a G to a T thus destroying the canonical G nucleotide of the splice acceptor site. There are several splice, nonsense and frameshift variants that have been associated with LQTS in the literature, including nearby splicing variants also in the c-terminus (922-1G>C; 1251+2T>C; 1514+1G>A). In total, this variant has not been seen in approximately 6,650 publicly available population and laboratory controls (including ~6,500 individuals of African American and European ancestry from NHLBI ESP dataset; 100 Caucasian individuals from GeneDx; and 50 individuals from Chung et al. 2007). There is a variant involving this same splice acceptor site seen in 6 individuals in ESP, however it is at the -8 position (thus unlikely to have the same effect as changing the canonical splice acceptor site). This variant has also not been observed in the 1000Genomes dataset or dbSNP as of October 31, 2013. This variant is currently present in HGMD and LOVD as a disease-causing mutation on the basis of the Chung et al. 2007 variant.

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