rs727503246
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PM2PP3PP1_Strong
This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys) variant has been identified in at least 40 individuals with HCM, including 1 with features of RCM (PS4; Brito 2005 PMID:16335287; Van Driest 2004 PMID:15358028; Perrot 2005 PMID:15856146; Theis 2009 PMID:19808356; Brito 2012 PMID:22857948; Zou 2013 PMID:23283745; Lopes 2013 PMID:23396983; Núñez 2013 PMID:23782526; Captur 2014 PMID:24704860; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Mademont-Soler 2017 PMID:28771489; Lu 2018 PMID:30165862; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregates with HCM in at least 10 relatives from 5 families (PP1_Strong; LMM pers. comm.; OMGL pers. comm.; Stanford Inherited Heart Center pers. comm.). This variant was also reported to segregate with disease in a family with HCM, although details were not provided (Brito 2012 PMID:22857948). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant alters protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Armel 2010 PMID:19913502; Wolny 2013 PMID:24047955). 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 (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014400/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYH7 | NM_000257.4 | c.4066G>A | p.Glu1356Lys | missense_variant | Exon 30 of 40 | ENST00000355349.4 | NP_000248.2 | |
| MYH7 | NM_001407004.1 | c.4066G>A | p.Glu1356Lys | missense_variant | Exon 29 of 39 | NP_001393933.1 | ||
| MIR208B | NR_030624.1 | n.-250G>A | upstream_gene_variant |
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461348Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726986
GnomAD4 genome 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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In vivo studies suggested this variant may lead to reduced sarcomere incorporation of myosin, but adverse effects on muscle contraction were not observed (PMID: 24047955); In vitro functional analysis demonstrated 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 (PMID: 19913502); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25961035, 15856146, 15358028, 23782526, 32894683, 28687478, 25125180, 23396983, 25649125, 26688388, 19808356, 23074333, 22857948, 24704860, 27532257, 27247418, 29300372, 23283745, 20800588, 25351510, 28408708, 28771489, 30165862, 31737537, 31199839, 32344918, 16335287, 34352619, 34428338, 35050212, 33658040, 32686758, 28615295, 33407484, 30297972, 35653365, 28193612, 34542152, 36291626, 19913502, 24047955) -
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). -
Hypertrophic cardiomyopathy Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1356 of the MYH7 protein (p.Glu1356Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 15856146, 19913502, 20800588, 22857948). ClinVar contains an entry for this variant (Variation ID: 164294). 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: 24047955). For these reasons, this variant has been classified as Pathogenic. -
The NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys) variant has been identified in at least 40 individuals with HCM, including 1 with features of RCM (PS4; Brito 2005 PMID: 16335287; Van Driest 2004 PMID: 15358028; Perrot 2005 PMID: 15856146; Theis 2009 PMID: 19808356; Brito 2012 PMID: 22857948; Zou 2013 PMID: 23283745; Lopes 2013 PMID: 23396983; Núñez 2013 PMID: 23782526; Captur 2014 PMID: 24704860; Homburger 2016 PMID: 27247418; Walsh 2017 PMID: 27532257; Mademont-Soler 2017 PMID: 28771489; Lu 2018 PMID: 30165862; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregates with HCM in at least 10 relatives from 5 families (PP1_Strong; LMM pers. comm.; OMGL pers. comm.; Stanford Inherited Heart Center pers. comm.). This variant was also reported to segregate with disease in a family with HCM, although details were not provided (Brito 2012 PMID: 22857948). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant alters protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Armel 2010 PMID: 19913502; Wolny 2013 PMID: 24047955). 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 (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PP3. -
Hypertrophic cardiomyopathy 1 Pathogenic:2
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.41 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.86 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538 /PMID: 9288758 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10879615, 9288758). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11977178). Different missense changes at the same codon (p.Met694Ile, p.Met694Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002539 /PMID: 23031807, 9288094 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
This MYH7 Glu1356Lys variant has previously been identified in >15 unrelated HCM cases (see references, ClinVar submissions). The variant has also been reported to segregate in 2 affected families (Standford University, Pers 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 results in improper sarcomeric incorporation however no adverse effects on muscle contraction were observed (Wolny M, et al., 2013). We identified this variant in 2 probands diagnosed with HCM (Ingles et al., 2017; Ross et al., 2017). MYH7 Glu1356Lys is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict the variant to be deleterious. In summary, based on this information, we classify MYH7 Glu1356Lys as "pathogenic". -
Cardiomyopathy Pathogenic:1
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 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 reported to segregate with disease in a family although detailed data are not available (PMID: 22857948). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.E1356K pathogenic mutation (also known as c.4066G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4066. The glutamic acid at codon 1356 is replaced by lysine, an amino acid with similar properties. This variant has been reported in several patients with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in several families (Van Driest SL et al. J Am Coll Cardiol. 2004;44:602-10; Perrot A et al. J Mol Med. 2005;83:468-77; Millat G et al. Clin Chim Acta. 2010;411:1983-91; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Homburger JR et al. Proc Natl Acad Sci U.S.A. 2016;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; external communication). In functional in vitro and in vivo analyses, this variant has been suggested to adversely affect thick filament assembly in the sarcomere; however, the clinical impact of these findings has not been determined (Armel TZ et al. Biochem Biophys Res Commun. 2010;391:352-6; Wolny M et al. J Biol Chem. 2013;288:31952-62). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at