Description
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1768Lys, E1768K, (c.5302G>A) in the MYH7 gene. We had initially classified this variant as likely disease causing, however, given the weak case data and the lack of Asian controls, we reclassified it to variant of uncertain significance, probably disease causing in 2014. We now have Asian frequency data from ExAC showing it is rare in that population. Thus we are increasingly feel it is more likely that this variant is in fact disease causing, however it remains classified as a variant of uncertain significance, probably disease. An additional case would probably shift it to likely disease causing. The variant has been seen in at least three patients and possibly as many as five presumably unrelated patients with HCM, not including this patient. Van Driest et al., 2004 reported the variant in a cohort of 350 individuals with HCM, with no specific case data available for this variant, including ancestry data. Bos et al (2014) reported the variant in two patients with HCM in their Mayo cohort who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and with the clinical labs since some of these patients likely underwent clinical genetic testing. These two cases also likely overlap with two of the three reported by Kapplinger et al (2014) since that dataset includes Mayo cases and patients referred to Transgenomic for genetic testing. Unfortunately phenotypic data is not provided and so we cannot confirm if cases tested at Transgenomic had HCM. This variant has also been seen in another individual in our center with HCM, also of Asian ancestry. LMM's ClinVar assertion is "uncertain significance", with the following data: "The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM and in 1 affected relative with syncope. It was absent from large population studies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and across evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain." This variant is in the rod portion of MYH7 (exons 24-40) No segregation data is available. This variant changes a polar, acidic glutamic acid to a polar basic lysine. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts it to be disease causing. The glutamic acid at codon 1768 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with cardiomyopathy at nearby codons (Leu1769Met, Klassen et al 2008; Ala1766Thr, Girolamni et al 2006). The variant was reported online in 1 of 60,705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 24th, 2015). The phenotype of that individual 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was not observed in the following laboratory and published control samples: GeneDx reports it was not seen in 304 control individuals, Van Driest et al. reports it was not seen in 400 control alleles.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | not provided | not provided | not provided | not provided | | 4 | not provided | not provided | not provided |
