Submissions for variant NM_000238.4(KCNH2):c.422C>T (p.Pro141Leu)

gnomAD frequency: 0.00007  dbSNP: rs199472864

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058233	SCV000234059	likely benign	not provided	2024-05-10	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181756	SCV000539437	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.2% (27/11562) Latino chromosomes
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148539	SCV000555896	likely benign	Long QT syndrome	2024-12-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620293	SCV000737402	likely benign	Cardiovascular phenotype	2016-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000148539	SCV000740339	uncertain significance	Long QT syndrome	2016-11-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000058233	SCV000842497	likely benign	not provided	2017-11-03	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853031	SCV000995788	likely benign	Hypertrophic cardiomyopathy	2018-11-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000988005	SCV001137551	benign	Long QT syndrome 2	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988005	SCV001321523	likely benign	Long QT syndrome 2	2018-01-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001841759	SCV001349844	likely benign	Cardiac arrhythmia	2018-11-20	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058233	SCV000089753	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19716085).
CSER _CC_NCGL, University of Washington	RCV000148539	SCV000190252	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000058233	SCV000924816	uncertain significance	not provided	2017-04-10	no assertion criteria provided	provider interpretation	Detected in a teenage Latina female with a history of syncope that appears consistent with vasovagal syncope. Testing was done at GeneDx. p.Pro141Leu in exon 3 of the KCNH2 gene (NM_000238.2) Chromosome position 7:150656710 G / A Assessment: There is not enough confidence in the Pro141Leu variant to use it for diagnosis or for predictive genetic testing in family members. In 2014, GeneDx classified this as a Disease-Causing Mutation. Currently, however, GeneDx classifies it as a Variant of Unknown Significance (VUS) in ClinVar, as does Harvard's Laboratory for Molecular Medicine. Based on the information reviewed below, we classify it as VUS, probably benign, given that it is found at relatively high frequency (0.2% allele frequency) in the Latino general population, which is our patient's ancestry. This would mean that 1 out of every 250 people with Latino ancestry carries this variant, whereas the frequency of LQTS in the general population is ten times less than this (~1/2500 people). The variant was reported in 2 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of solid diagnostic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). There is no published segregation data. However: GeneDx reports in ClinVar that the variant did not segregate with the LQTS phenotype in a family tested at GeneDx. This is a conservative amino acid change, resulting in the replacement of a nonpolar Proline with a nonpolar Leucine in the N-terminal PAC regulatory domain of the protein. Proline at this location is poorly conserved across vertebrate species, and Leucine is in fact the default amino acid in at least 7 species for which we have data. No missense variation at nearby residues (+/- 10) is listed as Likely Pathogenic or Pathogenic in ClinVar as of 4/10/2017, which may support the notion that this region of the protein is tolerant of change. GeneDx reports in ClinVar that in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. This variant was reported in 78 out of 138,488 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 70/17,210 individuals with Latino ancestry (for the highest allele frequency: 0.2%). It was also observed in 5 non-Finnish European, 1 South Asian, 1 African, and 1 "Other" ancestry. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. In terms of published controls: It was not observed by Kapplinger et al. (2009) in 1,300 ostensibly healthy volunteers (2,600 reference alleles; 47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other)