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.Arg453His (c.1358G>A) in the MYH7 gene. Given this variant is seen in several unrelated families with HCM in the literature, and its rarity in the general population, we consider this variant to be likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 7 unrelated cases of HCM (not including this patient's family). It is currently listed in ClinVar, where the Laboratory for Molecular Medicine (LMM) classifies it as “likely pathogenic”: ClinVar accession RCV000035718.2. Haluza et al. (2001) reported the variant in a 23 yo male with obstructive HCM who was found to be compound heterozygous for this variant and MYH7 p.Arg403Trp (which we consider very likely disease causing). Interestingly, this p.Arg453His variant was found to be de novo in that patient, making the significance of p.Arg453His somewhat uncertain at the time. The authors do discuss the male patient’s early presentation, which consisted of multiple syncopal events by the age of 17, and at 23 years of age development of heart failure. He reportedly had no family history of HCM. Yu et al. (2005) reported this variant in one Australian patient with HCM. 100 ethnicity matched controls were screened. Millat et al (2010) reported this variant in a patient with HCM. Ancestry is not specified but the authors are from a French group, and they screened French control chromosomes when evaluating novel variants as part of their study. Teirlinck et al 2012 does report this variant in an individual with HCM, but it is unclear if this represents the same individual as reported by Millat et al 2010 (same authors and appears to be the same French cohort). Olivotto et al. (2011) reported this variant in a 15 yo female patient with HCM. Santos et al (2012) identified this variant in a Portuguese patient with HCM, who also was identified with another missense variant in MYH7: p. c.2644 C > G; p.Gln882Glu. The authors state that all patients with multiple mutations had septal hypertrophy and a family history of HCM; but the data for this specific patient is not available in their table 2 (which describes this info on the cohort). The authors screened 100 controls. Marsiglia et al (2013) identified this variant in a Brazilian patient with HCM. Finally, the Laboratory for Molecular Medicine reports that they have seen this variant in one African American individual with HCM previously tested by their laboratory (LMM, unpublished data- ClinVar). There is no available segregation data on the variant. In silico analysis with Mutation Taster and PolyPhen-2 predicts the variant to be damaging. The Arginine at codon 453 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg453Cys and Arg453Leu) and nearby codons (p.Lys450Glu, p.Lys450Thr). There is strong evidence supporting the pathogenicity of p.Arg453Cys (considered very likely disease causing by our team), providing additional evidence of the functional importance of this region. In total the variant has not been seen in approximately 60,200 published controls and individuals from publicly available population datasets. There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/9/15). Note that this dataset does not match the patient's ancestry (India). There is also no variation at codon 473 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of 9/3/2015).
| # | 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 | | 8 | not provided | not provided | not provided |
