ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys) (rs727503246)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584808 SCV000692494 pathogenic Familial hypertrophic cardiomyopathy 1 2017-03-09 criteria provided, single submitter research This MYH7 Glu1356Lys variant has previously been identified in at least 15 unrelated HCM cases (see references, ClinVar submissions) and was absent in over >150 controls, collectively (Perrot A, et al., 2005; Núñez L, et al., 2013). The variant has also been reported to segregate in 2 affected families (Standford University ClinVar:SCV000280345.1; per comm.). A biochemical and biophysical assay has shown that the variant destabilises the protein and impairs filament formation (Armel TZ & Leinwand LA, 2010), whereas expression in adult rat cardiomyocytes suggests that this variant alters the alpha-helical structure, resulting in improper sarcomeric incorporation (Wolny M, et al., 2013). We identified this variant in 1 individual diagnosed with HCM at the age of 24 years, with asymmetric hypertrophy. There is no family history of disease and/or sudden cardiac death. MYH7 Glu1356Lys is absent in general population databases including 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Glutamic acid (Glu) at position 1356 is highly conserved across distantly related species, and computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict the variant to be deleterious. Additionally, Polyphen-HCM (Jordan DM, et al., 2011) predicts that this MYH7 variant is causative of the disease. In summary, based on this information, we classify MYH7 Glu1356Lys as "pathogenic".
Ambry Genetics RCV000619582 SCV000740076 likely pathogenic Cardiovascular phenotype 2017-10-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Blueprint Genetics RCV000223815 SCV000927656 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000461192 SCV000564448 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.4066G>A (p.Glu1356Lys) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:24704860; PMID:23396983; PMID:19808356; PMID:22857948; PMID:15856146; PMID:27532257; AGCMC Sydney ClinVar SCV000692494.1; Partners LMM ClinVar SCV000199128.3; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 5 affected individuals (PP1_Moderate; Partners LMM ClinVar SCV000199128.3; SHaRe consortium, PMID: 30297972). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PP1_Moderate; PP3
Color RCV000772181 SCV000905298 likely pathogenic Cardiomyopathy 2018-08-27 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant is located in the LMM domain of the MYH7 protein, C-terminal tail region that forms the thick filament backbone and interacts with other proteins. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have suggested that this variant may thermodynamically destabilize the protein (PMID: 19913502) and reduce incorporation of the mutant protein into the sarcomeres (PMID: 24047955). However, the variant did not significantly affected muscle contraction (PMID: 24047955). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 28771489, 23283745, 22857948, 20800588, 19808356, 15856146, 15358028) and said to segregate with disease in a family although detailed data are not available (PMID: 22857948). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV000223815 SCV000208565 likely pathogenic not provided 2018-12-21 criteria provided, single submitter clinical testing The E1356K likely pathogenic variant in the MYH7 gene has previously been reported in multiple individuals with LVH or HCM (Van Driest et al., 2004; Perrot et al., 2005; Theis et al., 2009; Brito et al., 2012; Lopes et al., 2013; Nunez et al., 2013; Zou et al., 2013; Captur et al., 2014; Chanavat et al., 2016). This variant has also been identified, both independently and/or in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. E1356K has been observed to segregate with a cardiomyopathy phenotype in multiple families (pers com. ClinGen EP). Brito et al. (2012) reported that this variant segregated with an HCM phenotype in affected relatives of a single proband, although specific details about the number of relatives, relationship, and clinical status were not provided. The E1356K variant is not observed in large population cohorts (Lek et al., 2016). E1356K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, in vitro functional analysis by Armel et al. (2010) showed that E1356K appears to induce decreased thermal stability and decreased ability to form filaments, though the filaments that did form were indistinguishable from wild-type and contraction was not significantly affected in comparison to wild-type. Wolny et al. (2013) suggested E1356K may lead to reduced sarcomere incorporation of myosin in vivo but did not observe any adverse effects on muscle contraction.In summary, E1356K in the MYH7 gene is interpreted as a likely pathogenic variant.
Invitae RCV000461192 SCV000546247 pathogenic Hypertrophic cardiomyopathy 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1356 of the MYH7 protein (p.Glu1356Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) . This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15856146 , 19913502, 20800588, 22857948). ClinVar contains an entry for this variant (Variation ID: 164294). Experimental studies have shown that this missense change affects the secondary structure of the MYH7 protein and interferes with its incorporation into thick filaments (PMID: 24047955). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151243 SCV000199128 uncertain significance not specified 2014-03-07 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223815 SCV000280345 likely pathogenic not provided 2012-01-18 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.Glu1356Lys (c. 4066G>A) in the MYH7 gene. We first reviewed this variant in June 2011, we reviewed it on 1/25/2012, adding additional control data. There was no new case data at that time. We last reviewed it on 4/17/13 adding additional control and case data. We are aware of a total of at least 4 presumably unrelated individuals who have this variant and have cardiomyopathy (not including this family). This variant has been reported in 4 unrelated individuals with HCM (Van Driest et al 2004, Millat et al 2010, Perrot et al 2005, Brito, 2011). Brito et al the variant segregated with disease, although specifics are not given. Theis et al (2009) also reported a case with this variant, however it may be the same case that was reported by Van Driest et al (2004). Moderate segregation data is available within our patient's family. This is a semi conservative amino acid change with a polar, negative glutamic acid replaced by a polar, positive lysine. Conservation analysis illustrates that glutamic acid is highly conserved across species at codon 1356 (Perrot et al 2005). There are no published disease associated variants within 10 codons upstream or downstream of this variant. Functional studies indicate that the presence of p.Glu1356Lys thermodynamically destabilizes the resulting myosin heavy chain protein and affecting its ability to form filaments and to function properly (Armel et al 2009). LMM informed me that a novel computational tool specific to sarcomere genes and based on PolyPhen predicts the variant to be pathogenic. This tool has a reported accuracy of 94% (Jordan 2011). In total, this variant was not observed in ~7,296 published controls, laboratory controls, and publicly available general population samples. Note that the family's ancestry is Asian, and few of these controls are matched to that ancestry. PGxHealth reports that they did not see this variant in 400 presumably healthy controls of mixed ethnic background. Perrot et al did not find the variant in 96 healthy volunteers of unspecified race. Brito did not find the variant in 100 additional samples of unspecified race. Van Driest et al did not identify the variant in 100 Caucasian and 100 African American controls. There is no variation at codon 1356 listed in dbSNP (as of 4/17/13). There are two entries for variant at codon 1356 listed in 1000 genomes, however one points to an HGMD entry and the other is rom COSMIC project (somatic mutations found in human cancers) (April 17th, 2013). There is also no variation at codon 1356 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 4/17/2013).

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