ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMIDs: 10753933, 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools but uninformative conservation with a moderate amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Ile19Phe) has been detected in individuals with LQTS (ClinVar, PMIDs: 32893267, 31520628). It has been reported as a VUS in ClinVar in a family with segregation evidence (personal communication). However, a study utilising an adapted version of the ACMG guidelines, has regarded it as likely pathogenic (PMID: 32893267). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been detected in at least two families with LQTS and regarded as a VUS, including a de novo occurrence in an individual with LQTS who also harbours a variant of uncertain significance with potential clinical relevance (VUS-3A) in KCNQ1 (PMID: 26669661; LOVD; VCGS cohort). A study utilising an adapted version of the ACMG guidelines, has regarded it as likely pathogenic (PMID: 32893267). (I) 0905 - No published segregation evidence has been identified for this variant. This variant has been reported in a family; however, no sufficient information was provided to inform segregation (PMID: 26669661; LOVD). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign