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. MYH7 p.Asp906Gly (c.2717A>G) Given the strong case data, strong segregation data, and absence in controls and the general population (reviewed below) we consider this variant very likely disease causing. The variant has been seen in at least 9 unrelated cases of HCM (not including this patient's family). There is strong segregation data. The Seidmans’ group included a kindred with this variant in a study on diastolic dysfunction in HCM (Ho et al 2002). Of 22 carriers studied, 9 had HCM. Alpert et al (2005) reported a family with this variant with 3 of 13 carriers having HCM. Two siblings from this family married two siblings from another family with HCM and a different MYH7 variant. Two offspring carried both variants and both had HCM. The Seidman group later reported a patient with apical HCM and this variant. His brother died suddenly and had evidence of HCM on autopsy (Arad et al 2005). This appears to be a different family than reported in Ho et al (2002). Ackerman's group observed the variant in 4 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). Those cases are presumably redundant with those in another paper by Ackerman’s group that included 5 HCM patients seen at Mayo or tested Transgenomics (Kapplinger et al 2014). McKenna’s group included a patient with HCM and this variant from their UK cohort in a paper on developmental structural differences in HCM (Captur et al 2014). Per their ClinVar submission, LMM considers the variant pathogenic (SCV000059468). The submission does not include any internal case data. 2 additional entries in ClinVar (OMIM and GeneDx) consider this variant pathogenic. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar score 0.375). Mutationtaster predicts it to be disease causing. The aspartate at codon 906 is not completely conserved across species. Other variants have been reported in association with disease at this codon (p.Asp906Asn (per ClinVar, LMM considers this of uncertain significance (SCV000059466, last reviewed by LMM in 2010)) and nearby codons (p.Asp900Gly, p.Gln907Lys, p.Leu908Val, p.Ile909Val). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. There is no variation at codon 906 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 3rd, 2014). Additionally, there is no variation at this codon in the ExAC dataset, which contains sequence data from ~65,000 individuals of varying ancestries from various exome sequencing cohorts (as of Feb 26, 2015). The variant is listed in dbSNP (rs267606908) with the only submission being disease-related (as of October 3rd, 2014). There is also no variation at this codon listed 1000 genomes (as of October 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bos et al 2014).
| # | 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 | | 9 | not provided | not provided | not provided |
