ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2206A>G (p.Ile736Val) (rs397516138)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035777 SCV000059428 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing The p.Ile736Val variant in MYH7 has been reported in the literature in 2 individ uals with HCM (Bos 2014; Homburger 2016; Alfares 2015; Walsh 2017). This variant has also been reported in ClinVar (VariationID: 42889). It has been identified in 2/111428 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516138). This variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jorda n 2011). In addition, the change from isoleucine (Ile) to valine (Val) has been seen in distantly related species. However, a different pathogenic variant invol ving the same codon (p.Ile736Thr) has been identified in multiple individuals wi th HCM, suggesting changes at this position may not be tolerated. In addition, t his variant lies in the head region of the protein. Missense variants in this re gion have been reported and statistically indicated to be more likely to cause d isease (Walsh 2016). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ile736Val variant is uncertain due to c onflicting data.
GeneDx RCV000225741 SCV000208454 likely pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing Although the I736V mutation in the MYH7 gene has not been been reported to our knowledge, several mutations at the same residue, I736L, I736M, and I736T, have been published in association with HCM (Millat G et al., 2010; Koga Y et al., 1996; Erdmann J et al., 2003; Mohiddin S et al., 2003; Ingles J et al., 2005; Perrot A et al., 2005). Koga Y et al. (1996) reported I736M was present in three affected family members with HCM and was absent from 100 healthy Japanese controls. Ingles et al. (2005) reported that I736T mutation co-segregated with HCM in affected family members. I736T was also identified in one affected individual with a family history of HCM (Mohiddin S et al., 2003). Collectively I736T was not observed in more than 300 healthy control chromosomes (Erdmann J et al., 2003; Mohiddin S et al., 2003; Ingles J et al., 2005). I736V mutation was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, I736V in the MYH7 gene is interpreted as a likely disease-causing mutation.
Blueprint Genetics RCV000225741 SCV000927919 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185533 SCV000238408 uncertain significance Familial hypertrophic cardiomyopathy 1 2014-07-17 no assertion criteria provided research This test identified a previously reported variant (c.2206T>C;p.Ile736Val) in the MYH7 gene. This gene is associated with different cardiac conditions including familial hypertrophic cardiomyopathy. The p.Ile736Val variant has been reported in one patient with hypertrophic cardiomyopathy (Bos et al. 2014, PMID: 24793961). Additionally, other variants with different amino acid change (at the same position) have been reported in individuals with familial hypertrophic cardiomyopathy (Koga et al. 1996, PMID: 8951566; Erdmann et al. 2003, PMID: 12974739; Millat et al. 2010, PMID: 20800588).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000035777 SCV000280315 uncertain significance not specified 2014-12-22 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.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) The variant has been seen in at least 2 unrelated cases of HCM (not including this patient's family). There is no segregation data available. GeneDx notes that the variant is novel, however I was able to find reports of it online. The variant is listed in ClinVar with a submission from LMM (SCV000059428). The last reviewed in 2008 and classified it as a variant of uncertain significance. It looks like they saw this in one family, though specific phenotypic details are not provided. We have never seen this variant. The variant is also listed online in the Seidmans' database (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_Ile736Val.html), noting their group has seen it in a patient with left ventricular wall thickness of 2.0 cm and a diagnosis of HCM. It is likely that the LMM case and Seidmans' case overlap, given how closely those two groups work together. Dr. Ackerman's group reported 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). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.996). The isoleucine at codon 736 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile736Thr, which we classify as likely disease causing and p.Ile736Met, p.Ile736Leu) and nearby codons (A728V, A729P, I730T, P731L, P731S, G733R, G733E, Q734E, Q734P, G741A, G741R, G741W, A742E, E743D, per GeneDx report, referencing HGMD). 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 736 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). The variant is listed in dbSNP (rs397516138), with the only submission being from LMM (as of July 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bot et al 2014).

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