Submissions for variant NM_000219.6(KCNE1):c.12dup (p.Asn5Ter)

dbSNP: rs1131691762

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493904	SCV000582777	pathogenic	not provided	2015-10-12	criteria provided, single submitter	clinical testing	The c.12dupT variant in the KCNE1 gene has been observed in an individual referred for LQTS testing and was absent from over 2,600 reference alleles (Kapplinger et al., 2009). This variant causes a shift in reading frame starting at codon Asparagine 5, which creates a premature stop codon at this position of the new reading frame, denoted p.N5X. This pathogenic variant is expected to result in an abnormal, truncated protein product. Other frameshift variants in the KCNE1 gene have been reported in HGMD in association with arrhythmia (Stenson et al., 2014). Furthermore, the c.12dupT variant 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.In summary, c.12dupT in the KCNE1 gene is interpreted as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694374	SCV000822817	pathogenic	Long QT syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn5*) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 amino acid(s) of the KCNE1 protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with long-QT syndrome (PMID: 19716085). This variant is also known as 13insT. ClinVar contains an entry for this variant (Variation ID: 430060). This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Asp76Asn) have been determined to be pathogenic (PMID: 9354802, 24400172, 24606995). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000493904	SCV001447310	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002383948	SCV002689825	pathogenic	Cardiovascular phenotype	2023-06-07	criteria provided, single submitter	clinical testing	The c.12dupT pathogenic mutation, located in coding exon 1 of the KCNE1 gene, results from a duplication of T at nucleotide position 12, causing a translational frameshift with a predicted alternate stop codon (p.N5*). This variant has been reported in several long QT and/or Jervell and Lange-Nielsen syndrome cohorts, but clinical information was limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Faridi R et al. Hum Mutat, 2019 Feb;40:162-176; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Roberts JD et al. Circulation, 2020 Feb;141:429-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. However, pathogenic and likely pathogenic KCNE1 variants typically exhibit low penetrance in the heterozygous state and may represent risk factors that manifest clinically only in the presence of additional genetic or environmental factors (Roberts JD et al. Circulation. 2020 02;141(6):429-439).
Fulgent Genetics, Fulgent Genetics	RCV002475977	SCV002785692	pathogenic	Jervell and Lange-Nielsen syndrome 2; Long QT syndrome 5	2021-07-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787804	SCV005398304	pathogenic	Jervell and Lange-Nielsen syndrome 2	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Jervell and Lange-Nielsen syndrome 2 (MIM#612347) and long QT syndrome 5 (MIM#613695) (PMID: 31941373). This gene has limited evidence for association with long QT syndrome, however it has strong evidence for the association with acquired long QT syndrome (PanelApp Australia, PMID: 31983240, 35373836). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic and monoallelic variants in this gene have been associated with Jervell and Lange-Nielsen syndrome 2 (MIM#612347) and long QT syndrome 5 (MIM#613695), respectively. (I) 0112 - The condition associated with this gene has incomplete penetrance. Weak penetrance has been reported for KCNE1 variants associated with long QT syndrome (PMID: 31941373). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant truncates the annotated ISK channel (DECIPHER). (I) 0701 - Other downstream protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1207 - Parental origin of the variant is unresolved. Duo analysis indicates that this individual's mother is heterozygous. One allele has been inherited from the mother, however the father was not tested (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign