ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.422C>T (p.Pro141Leu) (rs199472864)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058233 SCV000234059 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing The P141L variant of uncertain significance in the KCNH2 gene has previously been reported in association with LQTS (Kapplinger et al., 2009; Adler et al., 2016). It has also been observed, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for LQTS genetic testing at GeneDx. However, this variant failed to segregate with disease in one affected relative. The P141L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, in-silico analysis suggests this variant is probably damaging to the protein structure/function. Nevertheless, the P141L variant is observed in 70/34,420 (0.2%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant in this population.
Laboratory for Molecular Medicine,Partners HealthCare 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
Invitae RCV000148539 SCV000555896 likely benign Long QT syndrome 2017-12-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620293 SCV000737402 likely benign Cardiovascular phenotype 2016-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
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 Inc 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
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 Medical Center 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)

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