Submissions for variant NM_172362.3(KCNH1):c.1069C>T (p.Arg357Trp)

dbSNP: rs2102561827

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001984299	SCV002278075	pathogenic	not provided	2024-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 357 of the KCNH1 protein (p.Arg357Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset epilepsy (PMID: 36285361). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1493344). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNH1 protein function. This variant disrupts the p.Arg357 amino acid residue in KCNH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23020937, 26264464). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Dept of Pediatrics, Guizhou Children's Hospital, Affiliated Hospital of Zunyi Medical University	RCV002254215	SCV002524075	likely pathogenic	Temple-Baraitser syndrome		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002254215	SCV003920990	pathogenic	Temple-Baraitser syndrome	2023-03-09	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PS4_MOD,PS2_SUP,PM2_SUP,PP2,PP3