ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4031G>A (p.Arg1344Gln) (rs797045097)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211873 SCV000245640 uncertain significance not specified 2016-11-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1344Gl n variant in MYH7 has been reported in at least 2 individuals with HCM (Marsigli a 2013, Bos 2014), and has been identified by our laboratory in 1 individual wit h HCM. It was absent from large population studies. Arginine (Arg) at position 1 344 is highly conserved in mammals and evolutionarily distant species and the ch ange to glutamine (Gln) was predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). Additional computational a nalysis suggests this variant may create an alternative splice site, which could result in the in-frame deletion of 20 amino acids. However, this information is not predictive enough to determine pathogenicity. In summary, while there is so me suspicion for a pathogenic role, the clinical significance of the p.Arg1344Gl n variant is uncertain.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000190606 SCV000256119 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223729 SCV000280344 likely pathogenic not provided 2011-11-03 no assertion criteria provided clinical testing 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.Arg1344Gln (c.4031G>A) in the MYH7 gene. Given the newly reported presence in cases around the world, the absence in unselected populations, we consider this variant likely disease causing. When the patient first had genetic testing the variant was novel, with no published data. Ackerman's group observed the variant in one patient 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 may overlap with prior reports by Ackerman's group (ex. van Driest et al 2005). Arad et al (2014) reported the variant in a patient with HCM in their Israeli cohort. The patient presented at 13yo and had "massive LVH" (also described as "severe distal hypertrophy"), severe heart failure, and, reportedly, growth delay. It is unclear what genes were sequenced. Marsiglia et al (2013) observed the variant in one of 268 unrelated patients with HCM in their Brazilian cohort. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2. There is no ClinVar entry (as of July 22nd, 2015) and there are no other cases in SHaRe. In silico analysis with Polyphen predicts this variant as probably damaging with a score of 0.984. MutationTaster predicts this variant to be disease causing with a score of 43. The Arganine at codon 1344 is completely conserved across species and isoforms. A polar positive Arginine is replaced with a polar neutral Glutamine. Another variant, p.Arg1344Trp has been reported with disease and is in ClinVar as pathogenic by GeneDx and a variant of uncertain significance by LMM. The variant is not listed in dbSNP or 1000 genomes (as of June 20, 2013). The variant is also not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,500 Caucasian and African American individuals (as of June 20, 2013). Bos et al (2014) did not observe the variant in 200 "ostensibly healthy" individuals. This variant is not listed 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 July 22nd, 2015). However, another variant at that codon (p.Arg1344Trp) is present in 2 of 60,278 individuals.

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