chr14-23427723-C-G
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_ModeratePS4PP3PM1PM2
This summary comes from the ClinGen Evidence Repository: The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID:30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011186/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- dilated cardiomyopathy 1SInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- MYH7-related skeletal myopathyInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- myopathy, myosin storage, autosomal recessiveInheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- myopathy, myosin storage, autosomal dominantInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- congenital myopathy 7A, myosin storage, autosomal dominantInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Ebstein anomalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hyaline body myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- left ventricular noncompactionInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- congenital heart diseaseInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYH7 | ENST00000355349.4 | c.1750G>C | p.Gly584Arg | missense_variant | Exon 16 of 40 | 1 | NM_000257.4 | ENSP00000347507.3 | ||
| MYH7 | ENST00000713768.1 | c.1750G>C | p.Gly584Arg | missense_variant | Exon 16 of 41 | ENSP00000519070.1 | ||||
| MYH7 | ENST00000713769.1 | c.1750G>C | p.Gly584Arg | missense_variant | Exon 15 of 39 | ENSP00000519071.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251490 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727248 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6
The MYH7 c.1750G>C; p.Gly584Arg variant (rs121913626, ClinVar Variation ID: 14090) is a common pathogenic variant reported in the literature in numerous individuals affected with hypertrophic cardiomyopathy (Marsiglia 2013, Nier 1999, Walsh 2017, Watkins 1992). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.922). Based on available information, this variant is considered to be pathogenic. References: Marsiglia JD et al. Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. Am Heart J. 2013 Oct;166(4):775-82. PMID: 24093860. Nier V et al. Variability in the ratio of mutant to wildtype myosin heavy chain present in the soleus muscle of patients with familial hypertrophic cardiomyopathy. A new approach for the quantification of mutant to wildtype protein. FEBS Lett. 1999 Nov 19;461(3):246-52. PMID: 10567705. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. Watkins H et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992 Apr 23;326(17):1108-14. PMID: 1552912.
Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (ClinVar Variant ID# 14090; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies demonstrate that this variant causes myofibril disarray in embryonic chicken cardiomyocytes (Wang et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8250038, 7731997, 9062359, 21769673, 23408646, 27639548, 27247418, 1552912, 8335820, 22429680, 24093860, 28606303, 28166811, 21310275, 27532257, 25611685, 28193612, 29300372, 10567705, 30275503, 31447099, 12953063)
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. MYH7 c.1750G>C p.Gly584Arg g.23896932C>G (chr14.GRCh37) Seen in 1 pt with HCM in our center. First reviewed 4/1/2013, re-reviewed 1 oct 2014 While the variant has been seen in many cases of cardiomyopathy, we consider it likely pathogenic instead of very likely pathogenic because of the absence of a large number of controls matching the published cases (which are nearly all Portuguese) as well as the lack of strong segregation data or animal model data. In total this variant has been seen in at least 29 unrelated individuals with HCM (including one patient in our center) with weak segregation data in two families. We have seen the variant once in our center, in a Portuguese man who was diagnosed at 58 years of age with HCM, with a septum of 3.1 cm. This variant was initially reported in two families with HCM (Watkins et al 1993). In one family a haplotype block containing the variant segregated with 3 affected individuals, and in the second family it segregated with 2 affecteds. Both families were of Portuguese origin, and they had identical haplotypes thus suggesting p.Gly584Arg is a founder variant in this population. In a study on 80 Portuguese patients with HCM Santos et al (2012) observed the variant in one individual with HCM. Vieira et al (1995) appear to have assessed the prevalence of this variant in a Portuguese population. The manuscript is in Portuguese. Using google translate we were able to ascertain that they did not observe this variant in their cohort, but unfortunately it is unclear how many patients they studied or if they published controls. GeneDx shared that they have seen this variant in two other probands, one Caucasian and the other Portuguese. I also contacted the Laboratory for Molecular Medicine and they shared that they have seen it in 23 cases (2013). Unfortunately they have no segregation data nor do they have detailed ancestry data. They shared that most of the cases were listed as Caucasian without further specifics, though they did notice that many of the patients have Portuguese names. Carolyn Ho’s group included a patient with this variant in a paper on extracellular volume expansion, however it is unclear if that individual had hypertrophy or not (Ho et al 2013). In addition, that case likely overlaps with the LMM’s cases. No ancestry or segregation data was reported. Per their ClinVar submissions, LMM classifies it as likely pathogenic (SCV000059395). This is a semi conservative amino acid change with a nonpolar, neutral Glycine replaced with a polar, positively charged Arginine. In silico analysis (SIFT, PolyPhen2, mutationtaster) predicts the amino acid change to be deleterious/probably damaging to the resulting protein. The Laboratory of Molecular Medicine shared that their sarcomere-specific PolyPhen predicts the variant to be pathogenic and the lab notes that the pathogenic prediction is estimated to be correct 94% of the time (Jordan et al 2011). Additional variants at the same codon (p.Gly584Ser (Erdmann et al 2003, per ClinVar LMM classifies as likely pathogenic (SCV000059394)) and nearby codons (p.His576Arg, p.Ala583Val, p.Asp587Val) have been reported in association with cardiomyopathy (per the GeneDx report citing HGMD). Wang et al (2003) observed dramatic myofibril disarray after introducing the variant into chicken embryonic myocytes. Nier et al (1999) studied muscle fibers from a patient with p.Gly584Arg and observed that only 12% of all myosin in the sarcomeres was the variant version. However they did not observe any impact on sarcomere function. In total the variant has not been seen in ~6600 published controls and publicly available general population samples
PP1_moderate, PP3, PM1, PM2, PS4
Hypertrophic cardiomyopathy Pathogenic:3
The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3
The p.Gly584Arg variant in MYH7 has been reported in at least 8 individuals with HCM (Watkins 1993 PMID:8250038, Nier 1999 PMID:10567705, Santos 2012 PMID: 22429680, Marsiglia 2013 PMID:24093860) and has been identified by our laboratory in >20 individuals with HCM. Furthermore, this variant segregated with disease in 5 affected members (including 1 obligate carrier) from 4 families (Watkins 1993 PMID:8250038, LMM data). It has also been identified in 0.001% (1/113768) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID:27532257). In vitro functional studies support an impact on protein function (Fujita 1998 PMID:9062359, Wang 2003 PMID:12953063) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, this variant was classified as pathogenic on 12/15/2016 by the ClinGen-approved Cardiomyopathy expert panel (Variation ID 14090). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Moderate, PM2_supporting, PM1, PS3_Supporting, PP3.
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 584 of the MYH7 protein (p.Gly584Arg). This variant is present in population databases (rs121913626, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8250038, 22429680, 24093860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14090). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 12953063). This variant disrupts the p.Gly584 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 23283745, 24510615, 26187847). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Hypertrophic cardiomyopathy 1 Pathogenic:3
The MYH7 c.1750G>C p.(Gly584Arg) missense variant has been observed in more than ten individuals with a phenotype consistent with hypertrophic cardiomyopathy, and has been shown to segregate with disease in multiple families (PMID: 8250038, 24093860, 30297972). Additionally, a different amino acid substitution at the same codon p.(Gly584Ser) has been reported in individuals with hypertrophic cardiomyopathy. Functional studies conducted in non-human cells demonstrated that this variant impacts cytoskeletal organization in cardiomyocytes (PMID: 12953063). This variant is not observed at a significant frequency in version 2.1.1 or version 4.1.0 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1750G>C p.(Gly584Arg) is classified as pathogenic for hypertrophic cardiomyopathy.
Cardiovascular phenotype Pathogenic:2
PS4, PP1_strong, PM1, PM2, PM5, PP3
The p.G584R pathogenic mutation (also known as c.1750G>C), located in coding exon 14 of the MYH7 gene, results from a G to C substitution at nucleotide position 1750. The glycine at codon 584 is replaced by arginine, an amino acid with dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least one family (Solomon SD et al. J. Am. Coll. Cardiol., 1993 Aug;22:498-505; Watkins H et al. Am. J. Hum. Genet., 1993 Dec;53:1180-5; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203). Functional studies have suggested that this alteration leads to impaired function and increased myofibril disarray (Fujita H et al. J. Clin. Invest., 1997 Mar;99:1010-5; Wang Q et al. J. Cell. Sci., 2003 Oct;116:4227-38). Other variant(s) at the same codon,p.G584S (c.1750G>A), have been identified in individual(s) with features consistent with HCM (Erdmann J et al. Clin Genet. 2003;64(4):339-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiomyopathy Pathogenic:1
Computational scores
Source:
Splicing
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