Submissions for variant NM_000218.3(KCNQ1):c.1066_1071del (p.Gln356_Gln357del)

dbSNP: rs397508073

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229325	SCV001401767	uncertain significance	Long QT syndrome	2019-09-13	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. It is unclear how this variant impacts the function of this protein. This variant has been reported to segregate with long QT syndrome (LQTS) in a family and has also been reported in an independent individual that was referred for LQTS genetic testing (PMID: 14731347, 23098067). ClinVar contains an entry for this variant (Variation ID: 52947). This variant is not present in population databases (ExAC no frequency). This variant, c.1066_1071delCAGCAG, results in the deletion of 2 amino acid(s) of the KCNQ1 protein (p.Gln356_Gln357del), but otherwise preserves the integrity of the reading frame.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577802	SCV000679015	not provided	Long QT syndrome 1		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004537219	SCV004107301	likely pathogenic	KCNQ1-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The KCNQ1 c.1066_1071del6 variant is predicted to result in an in-frame deletion (p.Gln356_Gln357del). This variant was reported to segregate with Long QT syndrome in three individuals in a family (Liang et al. 2003. PubMed ID: 14731347). This variant was also documented in an unrelated individual referred for Long QT syndrome genetic testing (Stattin et al. 2012. PubMed ID: 23098067). This variant was also reported, along with a missense KCNQ1 variant, in an individual with Jervell and Lange-Nielsen syndrome (Cepeda-Nieto et al. 2021. PubMed ID: 34165182). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, such prediction programs are imperfect and cannot substitute for mRNA studies. This variant has not been reported in a large population database, indicating this variant is rare. At PreventionGenetics, this variant was found to segregate with Long QT syndrome in a family (internal data). Taken together, this variant is interpreted as likely pathogenic.