Submissions for variant NM_000218.3(KCNQ1):c.921+1G>T

dbSNP: rs397508130

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182134	SCV000234437	pathogenic	not provided	2013-06-21	criteria provided, single submitter	clinical testing	The c.921+1 G>T mutation has been reported previously in one individual referred for LQTS testing, and was absent from at least 400 control chromosomes in this study (Splawski I et al., 2000). Additionally, c.921+1 G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice donor site in intron 6 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the KCNQ1 gene have been reported in association with LQTS. In summary, c.921+1 G>T in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377884	SCV001575331	pathogenic	Long QT syndrome	2024-06-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the KCNQ1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of long QT syndrome and/or Jervell and Lange-Nielsen syndrome (PMID: 10973849; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53126). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002444508	SCV002682252	likely pathogenic	Cardiovascular phenotype	2021-10-12	criteria provided, single submitter	clinical testing	The c.921+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the KCNQ1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in a long QT syndrome cohort (Splawski I et al. Circulation, 2000 Sep;102:1178-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496705	SCV002814621	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2022-05-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001377884	SCV004840116	likely pathogenic	Long QT syndrome	2023-12-11	criteria provided, single submitter	clinical testing	The c.921+1G>T variant in the KCNQ1 gene is located at the canonical donor splice site in intron 6 and is predicted to disrupt mRNA splicing resulting in an absent or aberrant protein product (SpliceAI score: 1.00). This variant has been reported in at least one individual with long QT syndrome (PMID:10973849). Loss-of-function variants are a known disease mechanism of long QT syndrome due to defects in the KCNQ1 gene (PMID:19862833). This variant is reported in ClinVar (ID: 53126). This variant is absent in the general population database, gnomAD. Therefore, the c.921+1G>T variant in the KCNQ1 gene is classified as likely pathogenic.