Description
MYH7 Asp239Asn has been previously reported in multiple HCM cases (Walsh et al., 2017; Adler et al., 2016; Murphy et al., 2016; Garcia-Pavia et al., 2011; Kaski et al., 2009; Iascone et al., 2007) and has been found to segregate in their families (Garcia-Pavia et al., 2011; Ambry, ClinVar SCV000740109.2). We have also identified MYH7 Asp239Asn in a HCM proband (Ingles et al., 2017) as well as their 3 affected family members. This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000004. An in vitro functional study showed that the variant results in higher actin activated ATPase activity, higher actin gliding velocities and increased intrinsic force of the protein which results in hypercontractility (Adhikari et al., 2016). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In silico tools PolyPhen2 and MutationTaster predict this variant to be deleterious, however SIFT predicts it to be "Tolerated". Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been identified in at least 12 HCM probands without additional variants (PS4_moderate), shown to segregate strongly with disease across multiple families (PP1_Supporting), has been shown to have a damaging affect on protein in a functional study (PS3), it is located in a mutational hotspot (PM1) and is rare in the general population (PM2), therefore we classify MYH7 Asp239Asn as 'pathogenic'.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
