ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.1660del (p.Val554fs)

dbSNP: rs794728561
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002857762 SCV003229179 pathogenic Long QT syndrome 2023-05-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the KCNQ1 protein in which other variant(s) (p.Arg632Glnfs*20) have been determined to be pathogenic (PMID: 10024302, 16981927, 19825999, 23098067, 23631430, 25187895). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 2023188). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val554Cysfs*39) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 amino acid(s) of the KCNQ1 protein.
Ambry Genetics RCV003274058 SCV004007873 pathogenic Cardiovascular phenotype 2023-06-12 criteria provided, single submitter clinical testing The c.1660delG pathogenic mutation, located in coding exon 13 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 1660, causing a translational frameshift with a predicted alternate stop codon (p.V554Cfs*39). This alteration occurs at the 3' terminus of theKCNQ1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in a long QT syndrome cohort (Walsh R et al. Genet Med, 2021 Jan;23:47-58). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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