Submissions for variant NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)

dbSNP: rs886041300

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000354221	SCV000329665	pathogenic	not provided	2021-03-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32860008, 26264464, 26818738, 27267311, 28628100, 28867141, 31278258, 32581362, 33594261)
Ambry Genetics	RCV000624249	SCV000741482	pathogenic	Inborn genetic diseases	2016-04-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095720	SCV001251558	pathogenic	KCNH1-related disorders	2020-01-20	criteria provided, single submitter	clinical testing	The KCNH1 c.1070G>A (p.Arg357Gln) variant is a missense variant that has been reported in two studies, in which it is found in a heterozygous, de novo state in five unrelated individuals with KCNH1-related disorders (Bramswig et al. 2015; Fukai et al. 2016). The clinical presentation of the affected individuals includes global developmental delay, epilepsy, neonatal hypotonia, nail aplasia/hypoplasia, broad thumbs or toes, long great toes, and craniofacial dysmorphism. The p.Arg357Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg357Gln variant is classified as pathogenic for KCNH1-related disorders.
Centogene AG - the Rare Disease Company	RCV001251120	SCV001426487	pathogenic	Zimmermann-Laband syndrome 1		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262681	SCV001440632	likely pathogenic	Temple-Baraitser syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000354221	SCV001581542	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNH1 protein function. ClinVar contains an entry for this variant (Variation ID: 279981). This missense change has been observed in individual(s) with KCNH1-related conditions (PMID: 23020937, 26264464, 26818738). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the KCNH1 protein (p.Arg357Gln).
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000354221	SCV001760729	pathogenic	not provided	2020-05-27	criteria provided, single submitter	clinical testing
3billion	RCV001262681	SCV002058524	pathogenic	Temple-Baraitser syndrome	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 26818738, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279981, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.872, 3CNET: 0.808, PP3_P). A missense variant is a common mechanism associated with Temple-Baraitser syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001251120	SCV002820120	pathogenic	Zimmermann-Laband syndrome 1		criteria provided, single submitter	clinical testing	The missense variant p.R357Q in KCNH1 (NM_172362.3) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in multiple unrelated individuals as a de novo variant (Fukai R et al,Bramswig NC et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic.The p.R357Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R357Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 357 of KCNH1 is conserved in all mammalian species. The nucleotide c.1070 in KCNH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV001262681	SCV003919068	pathogenic	Temple-Baraitser syndrome	2023-04-20	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV001251120	SCV003921064	pathogenic	Zimmermann-Laband syndrome 1	2023-02-23	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS2_VSTR, PS4, PM5, PM2_SUP, PP2, PP3
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003573	SCV001161934	likely pathogenic	Seizure; Abnormal facial shape; Intellectual disability, severe		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000354221	SCV001958862	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000354221	SCV001970932	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274967	SCV002562811	pathogenic	Seizure		no assertion criteria provided	clinical testing