14-23424148-T-C

Position:

• chr14-23424148-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PM1 PM2 PP1_Moderate PS4

This summary comes from the ClinGen Evidence Repository: The c.2681A>G (p.Glu894Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:PMID:27532257; PMID:15358028; PMID:15858117; PMID:21511876; PMID:23396983; PMID:24510615; SHaRe consortium, PMID:30297972, Partners LMM ClinVar SCV000059463.5; AGCMC Sydney ClinVar SCV000212641.2; Invitae ClinVar SCV000253683.5). This variant segregated with disease in 6 affected individuals (PP1_Moderate: AGCMC Sydney ClinVar SCV000212641.2; Partners LMM ClinVar SCV000059463.5). 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/CA012832/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense, splice_region
• Scores: Splicing: ADA: 0.9396
• Clinical Significance: Pathogenic reviewed by expert panel P:14 U:1 O:1
• Conservation: PhyloP100: 7.78

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2681A>G	p.Glu894Gly	missense_variant, splice_region_variant	23/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2681A>G	p.Glu894Gly	missense_variant, splice_region_variant	22/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2681A>G	p.Glu894Gly	missense_variant, splice_region_variant	23/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461850 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 27, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 27, 2014	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.Glu894Gly (c.2681A>G) This variant has been seen in at least 15 unrelated cases of HCM (not including this patient). There is no published segregation data. Van Driest et al. (2004) observed this variant in 3 unrelated individuals with HCM. These three cases are likely redundant with a later reports by that group, however there does appear to be an additional case in those reports (Kapplinger et al 2014, Bos et al 2014). Yu et al. (2005) found this variant in 3 unrelated Australian probands with HCM. Gruner et al. (2011) reported it in one patient with apical HCM from their Toronto cohort. Captur et al (2014) included a patient with HCM and this variant in a study comparing imaging findings in carriers with and without left ventricular hypertrophy. Subjects were recruited from the UCL HCM clinic in London. We have seen this variant in one other patient with HCM in our center. She was diagnosed with HCM at 4 months of age and has a severe phenotype. She had a multi-gene sequencing panel with no other variants found. She has a strong family history of HCM. Presumably LMM and GeneDx have seen this variant in patients, since they have submitted it to Clinvar, however that data is not available in ClinVar. I spoke to LMM directly and they shared that they have seen the variant in 5 families with HCM and in one family another affected relative had the variant. Variation at nearby residues in MYH7 has been associated with cardiomyopathy, supporting the functional importance of this region of the protein: Leu889His, Ala893Val, Ala901Gly, Ala901Pro, Glu903Gly, Glu903Lys (HGMD via GeneDx). This is a non-conservative amino acid change from a negatively charged glutamic acid residue to a neutral, nonpolar glycine. The glutamic acid at codon 894 is highly conserved across 43/44 vertebrate species examined (it is a serine in lamprey). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.992. The Invitae report notes that 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)". This is an algorithm developed by LMM and their colleagues. In total this variant has not been seen in ~6800 individuals from published controls and publicly available population datasets. Van Driest et al. (2004) did not find it in 100 control individuals of Caucasian descent or 100 control individuals of African-American descent. Yu et al. (2005) did not find it in 100 ethnicity-matched control individuals. No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 4/1/2013). No variation at this codon is present in dbSNP or in 1000 genomes. GeneDx did not report internal controls. There is no variation at codon 984 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of March 24th, 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	Classified as pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar; Variation ID: 42922); 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: 18761664, 27532257, 29300372, 24704860, 25961035, 25351510, 26914223, 15358028, 15858117, 21511876, 15519027, 24510615, 23396983, 28408708, 27247418, 24793961, 28606303, 28615295, 25132132, 21310275, 32894683, 28193612) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 30, 2021	- -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The p.Glu894Gly variant in MYH7 has been identified in >15 individuals with HCM and segregated with disease in 5 affected relatives from 2 families (Van Driest 2004a, Van Driest 2004b, Yu 2005, Gruner 2011, Lopes 2013, Kapplinger 2014, LMM data, Agnes Ginges Centre for Molecular Cardiology data - ClinVar SCV000212641.1). One of these individuals had a second variant in MYBPC3 and presented at an earlier age with a more severe phenotype. This variant was absent from large population studies. Computational prediction tools and conservation analysis are consistent with pathogenicity. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In addition, this variant was classified as pathogenic on December 15, 2016 by the ClinGen-approved Inherited Cardiomyopathy expert panel (ClinVar SCV000564436.2). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and prevalence in affected individuals. ACMG/AMP Criteria applied: PS4; PM1; PM2; PP1_Moderate; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 894 of the MYH7 protein (p.Glu894Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 15858117, 21511876, 26914223, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 42922). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2681A>G (p.Glu894Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:PMID:27532257; PMID:15358028; PMID:15858117; PMID:21511876; PMID:23396983; PMID:24510615; SHaRe consortium, PMID: 30297972, Partners LMM ClinVar SCV000059463.5; AGCMC Sydney ClinVar SCV000212641.2; Invitae ClinVar SCV000253683.5). This variant segregated with disease in 6 affected individuals (PP1_Moderate: AGCMC Sydney ClinVar SCV000212641.2; Partners LMM ClinVar SCV000059463.5). 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 -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2023	This missense variant replaces glutamic acid with glycine at codon 894 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15519027, 15858117, 21511876, 23396983, 24793961, 25351510, 26914223, 27532257, 28408708, 28615295, 28790153, 29300372, 32228044, 32894683, 33495597, 34556856, 35026164, 29300372). It has been shown that this variant segregates with disease in 6 affected individuals from multiple families (PMID: 29300372). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy 1 Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 05-23-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Apr 10, 2017	This MYH7 Glu894Gly variant has previously been identified in multiple HCM cohorts (Yu B, et al., 2005; Gruner C, et al., 2011; Lopes LR, et al., 2013; Kapplinger JD, et al., 2014; Walsh R et al., 2017). This variant was first described by Van Driest et al. (2004) in multiple HCM patients, one of whom was a carrier of a second variant in MYBPC3 and presented with a more severe phenotype (Van Driest SL, et al., 2004). The MYH7 Glu894Gly variant is extremely rare in the general population; it is absent in both the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in 7 HCM probands in our cohort. Genetic analysis was available for 2 families. In one family the variant was shown to co-segregate with disease in 4 affected members. This family also carries a VUS (TNNT2 Arg278Cys). In the second family the variant was found to segregate to one other affected family member (5 meioses in total). Computational tools SIFT, PolyPhen-2 and MutationTaster predict the Glu894Gly variant to be deleterious. Additionally, Polyphen-HCM (Jordan DM, et al., 2011) predicts that MYH7 Glu894Gly is deleterious. Furthermore, we have recently published ancestry studies to show our unrelated probands share a common haplotype, suggesting this may be a founder in the Australian population (Ross SB et al. 2017). Based on this data we classify MYH7 Glu894Gly as "pathogenic". -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 02, 2019

The MYH7 c.2681A>G; p.Glu894Gly variant (rs397516161) is reported in the literature in multiple hypertrophic cardiomyopathy cohorts (Homburger 2016, Lopes 2013, Murphy 2016, Van Driest 2004, Walsh 2017, Yu 2005). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 42922), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 894 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant is found in the myosin head domain, in which missense variants are overrepresented in individuals with hypertrophic cardiomyopathy (Walsh 2017). Based on available information, the p.Glu894Gly variant is considered to be pathogenic. References: Homburger JR et al. Multidimensional structure-function relationships in human beta-cardiac myosin from population-scale genetic variation. Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6701-6. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Murphy SL et al. Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. J Cardiovasc Transl Res. 2016 Apr;9(2):153-61. Van Driest SL et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Aug 4;44(3):602-10. 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. Yu B et al. Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease. J Clin Pathol. 2005 May;58(5):479-85. -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The p.E894G pathogenic mutation (also known as c.2681A>G), located in coding exon 21 of the MYH7 gene, results from an A to G substitution at nucleotide position 2681. The glutamic acid at codon 894 is replaced by glycine, an amino acid with similar 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 USA, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in several individuals from various hypertrophic cardiomyopathy (HCM) cohorts (Van Driest SL et al. J. Am. Coll. Cardiol. 2004 Aug;44:602-10; Yu B et al. J. Clin. Pathol. 2005 May;58:479-85; Kapplinger JD et al. J Cardiovasc Transl Res. 2014 Apr;7:347-61; Lopes LR et al. J. Med. Genet. 2013 Apr;50:228-39, Gruner C et al. Circ Cardiovasc Genet. 2011 Jun; 4:288-95; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). In addition, this alteration has been described as an ancestral mutation in an Australian HCM cohort where it was seen in multiple individuals with HCM and in their affected family members (Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

MYH7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2023

The MYH7 c.2681A>G variant is predicted to result in the amino acid substitution p.Glu894Gly. This variant was reported in numerous individuals with hypertrophic cardiomyopathy (Van Driest et al. 2004. PubMed ID: 15358028; Yu et al. 2005. PubMed ID: 15858117; Table S1B, Walsh et al. 2017. PubMed ID: 27532257). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic for hypertrophic cardiomyopathy by the ClinGen Cardiomyopathy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/; Table S4, Kelly et al. 2018. PubMed ID: 29300372). This variant is interpreted as pathogenic. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.96
MutPred		0.76		Gain of catalytic residue at A893 (P = 0.0641);
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.68
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516161; hg19: chr14-23893357;