Submissions for variant NM_000238.4(KCNH2):c.188C>A (p.Pro63His)

gnomAD frequency: 0.00001  dbSNP: rs766379103

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181932	SCV000234235	likely pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Reported in association with LQTS (Lieve et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 22396785)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181932	SCV000696022	uncertain significance	not provided	2016-04-13	criteria provided, single submitter	clinical testing	Variant summary: The KCNH2 c.188C>A variant is a missense change that alters a conserved nucleotide, resulting in an amino acid change from a non-polar Pro to a positively charged His residue. 4/4 in silico tools predict deleterious outcome (SNPs&GO not captured due to low reliability index). However, at the time of classification, functional studies had not been carried out to confirm these in silico predictions. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0013% (1/79290 chromosomes tested), which does not exceed the maximal expected allele frequency for a pathogenic KCNH2 variant. Additionally, the variant of interest has been reported in at least 1 patient with LQTS from the literature and was classified by a clinical diagnostic center as Pathogenic. Furthermore, multiple nearby missense mutations, such as c.182A>G (p.Q61R), c.185G>A (p.R62Q), c.191G>A (p.C64Y), andc.192C>G (p.C64W), have been reported in association with LQTS, further supporting the functional importance of this region. However, additional clinical information and segregation data are needed to evaluate the clinical significance of this missense change with confidence. Taken together, the variant was classified as a VUS until more information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631676	SCV000752759	uncertain significance	Long QT syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 63 of the KCNH2 protein (p.Pro63His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 23631430; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200559). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000181932	SCV002502302	uncertain significance	not provided	2022-02-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408789	SCV002722483	likely pathogenic	Cardiovascular phenotype	2022-03-29	criteria provided, single submitter	clinical testing	The p.P63H variant (also known as c.188C>A), located in coding exon 2 of the KCNH2 gene, results from a C to A substitution at nucleotide position 188. The proline at codon 63 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in multiple individuals with a diagnosis of long QT syndrome (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Invitae pers. comm.; GeneDx pers. comm.; Ambry internal data). Additionally, this alteration has been predicted to be disruptive to the PAS domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.