ClinVar

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. Based on the strong case data, moderate segregation data, and sufficiently low frequency in general population samples, we consider this variant likely disease causing. In total this variant has been seen in 11 unrelated cases of MYH7-linked phenotypes (including one case in our center), with moderate segregation data in one family. In addition to patients with HCM, there is one patient with Ebstein’s and one patient with borderline hypertrophy with an abnormal papillary muscle anatomy and LVOT obstruction. We have seen this variant in one patient in our center, a Caucasian, non-Hispanic woman diagnosed with HCM at 71 years of age with a murmur first noted at 53 years of age. She underwent myectomy at 73 years of age. This variant was initially reported in one individual with HCM (van Driest et al 2004). That report included only sequencing of MYH7. However, a separate report by the same group reported on the incidence of multiple variants in this cohort after analysis of 9 sarcomere genes and based on that it appears this patient had only this one MYH7 variant (van Driest et al 2004). Ancestry data was not available. Laredo et al (2006) reported the variant in a family from their Spanish cohort, with some evidence of co-segregation; from 9 family members 2 had HCM and were genotype positive for the variant, 1 family member with HCM was not genotyped but was an obligate carrier (Laredo et al 2006). Three additional family members were found to be carriers, they had a normal phenotype (and were in their thirties). Garcia-Castro et al (2009) reported the variant in a single case of HCM from their Spanish cohort who underwent sequencing of 5 sarcomere genes. Given authors and recruitment site, this seems to overlap with a case later reported by Coto et al (2012) but not with the family reported by Laredo et al (2006). Postma et al (2010) reported one individual with this variant with Epstein’s anomaly but no hypertrophy from a cohort recruited in the Netherlands, the UK and Germany (of note, Ebstein's anomaly, often with noncompaction, has recently been associated with MYH7 variants (Budde et al 2007, Postma et al 2011, van Engelen et al 2011)). The Seidman group observed the variant in 1 of 1963 individuals from the Jackson Heart Study who underwent sequencing of eight sarcomere genes (Bick et al 2012). They note the following about that individual's phenotype: 52yo with LVWT 1.1 cm, LVDD 4.64 cm, LAD 4.24 cm, fractional shortening 0.37, 1 physical cardiovascular risk factor (not specified). Marsiglia et al (2014) observed the variant in 3 of 131 Brazilian patients with HCM who underwent sequencing of MYH7, MYBPC3, and TNNT2. Ackerman's group observed the variant in 2 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases likely overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and there is also a chance they overlap with internal cases from the clinical genetic testing labs. Ancestry data was not reported. Per their ClinVar submission (SCV000059557), LMM considers this variant to be of uncertain significance, based on the atypical presentation in the patient with Ebstein’s (perhaps this was before the MYH7-Ebstein’s link was reported), and the fact that most carriers in the Laredo et al family were mildly affected or unaffected. It also noted that LMM “detected this variant in 3 out of >2000 Caucasian probands, one of whom carried a second, pathogenic variant, and one only had borderline hypertrophy with an abnormal papillary muscle anatomy and LVOT obstruction (no diagnosis was available for the third proband).” It is notable that the majority of the cases with available ancestry data are from Spain and Brazil, presumably with overlapping ancestral roots. This could indicate a founder affect for a pathogenic variant or instead it may indicate that this is a common benign variant in these subgroups. However, given that Spanish and Portuguese people share substantial genetic ancestry with other Europeans (and at least a subset of Brazilian ancestry is European, primarily Portuguese), the European American data in NHLBI ESP is likely applicable. This is a semi conservative amino acid change with a polar, positive Lysine replaced with a polar, neutral Asparagine. A variant in a nearby codon (Ala1454Thr) has been reported to be associated with disease. Conservation analysis indicates that Lysine is highly conserved at codon 1459 down to C. elegans (Postma et al 2010). Polyphen2 predicts the variant to be probably damaging. Mutationtaster predicts it to be disease causing. I could find no other disease-associated variants at this codon (as of 8 Oct 2014 in ClinVar, dbSNP, Bos et al 2014 >1000 patient Mayo series). In total the variant has been seen in 1 of 7493 general population samples and published controls. The variant was not observed in 100 African American and 100 Caucasian control individuals by the Ackerman’s group (van Driest et al 2004, Bos et al 2014). Laredo et al did not observe the variant in 100 control individuals of unspecified ethnic background. Postma‘s group did not find the variant in 490 ethnically mixed controls. Garcia-Castro et al (2009) did not see the variant in 200 control individuals. In the 2008 report PGX did not disclose control data for this variant. The variant was reported online in 1 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of October 7, 2014). 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 this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is listed in dbSNP with submissions related to the NHLBI ESP data and a submission from “Goldsteinlab” (rs201307101, as of October 7, 2014).