ClinVar Miner

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

dbSNP: rs886041300
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Total submissions: 15
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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 RCV004547654 SCV001251558 pathogenic KCNH1-related disorder 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 Centre For Genomic Medicine, NCGM 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

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