ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4498C>T (p.Arg1500Trp) (rs45544633)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151238 SCV000199112 likely pathogenic Primary dilated cardiomyopathy 2017-08-29 criteria provided, single submitter clinical testing The p.Arg1500Trp variant in MYH7 has been reported in the heterozygous state in 2 adults with LVNC and at least 6 adults with DCM (Karkkainen 2004, Jerosch-Hero l 2008, Merlo 2013, Hazebroek 2015, ClinVar Variation ID 164284). It was also id entified in the homozygous state in 1 child with neonatal DCM (GeneDx personal c ommunication). Furthermore, the variant segregated with disease in 2 affected re latives from 1 family (Jerosch-Herol 2008) and was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg1500Trp variant may impact protein function (Armel 2010, Wolny 2013). However, these ty pes of assays may not accurately represent biological function. Additionally, th is variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to b e correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1500Trp var iant is likely pathogenic.
Invitae RCV000232679 SCV000284279 pathogenic Hypertrophic cardiomyopathy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1500 of the MYH7 protein (p.Arg1500Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with dilated cardiomyopathy, and there is some evidence suggestive of segregation with disease (PMID: 15556047, 18660445, 19412328, 24119082). ClinVar contains an entry for this variant (Variation ID: 164284). In an experimental study this variant was shown to affect protein stability (PMID: 19854198). Furthermore, a different missense substitution at this codon (p.Arg1500Pro) is known to be deleterious (PMID:15322983, 19854198, 22155079), indicating that the Arg residue is important for MYH7 protein function. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617211 SCV000737223 likely pathogenic Cardiovascular phenotype 2020-02-18 criteria provided, single submitter clinical testing The p.R1500W variant (also known as c.4498C>T), located in coding exon 30 of the MYH7 gene, results from a C to T substitution at nucleotide position 4498. The arginine at codon 1500 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several dilated cardiomyopathy (DCM) cohorts (Kärkkäinen S et al. Eur. J. Heart Fail. 2004;6:861-8; Hershberger RE et al. Clin Transl Sci. 2008;1:21-6​; Jerosch-Herold M et al. Am. J. Physiol. Heart Circ. Physiol. 2008;295:H1234-H1242; Merlo M et al. Clin Transl Sci. 2013;6:424-8; Forleo C et al. PLoS ONE. 2017;12:e0181842). In vitro studies suggest that this alteration has an impact on filament formation; however, the same effect was not reproduced in vivo (Armel TZ et al. J. Mol. Cell. Cardiol., 2010 May;48:1007-13; Buvoli M et al. J. Mol. Biol. 2012;415:807-18; Wolny M et al. J. Biol. Chem., 2013 Nov;288:31952-62). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770475 SCV000901918 likely pathogenic Cardiomyopathy 2017-06-12 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786165 SCV000924859 likely pathogenic not provided 2016-01-11 no assertion criteria provided provider interpretation

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.