14-23425970-C-T

Position:

• chr14-23425970-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP3 PM1 PM5 PM2 PP1_Strong PS4

This summary comes from the ClinGen Evidence Repository: The c.2156G>A (p.Arg719Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:7848441; PMID:16199542; PMID:15358028; PMID:18411228; Partners LMM ClinVar SCV000059421.5; AGCMC Sydney ClinVar SCV000212634.1; SHaRe consortium, PMID:30297972). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:7848441; Partners LMM ClinVar SCV000059421.5). 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). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2155C>T p.Arg719Trp ClinVar Variation ID 14104). 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; PP1_ Strong; PM1; PM2; PM5; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011785/MONDO:0005045/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 0.861

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 15 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2156G>A	p.Arg719Gln	missense_variant	19/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2156G>A	p.Arg719Gln	missense_variant	18/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2156G>A	p.Arg719Gln	missense_variant	19/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 06, 2022	The MYH7 c.2156G>A; p.Arg719Gln variant (rs121913641) is reported in the literature in multiple individuals and families with hypertrophic cardiomyopathy, and shown to co-segregate with disease (Burns 2017, Consevage 1994, Gonzalez-Quereda 2020, Robyns 2020, Walsh 2017). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 14107). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 719 is highly conserved, and computational analyses are uncertain whether this variant is benign or deleterious (REVEL: 0.694). Based on available information, this variant is considered to be pathogenic. References: Burns C et al. Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. Circ Cardiovasc Genet. 2017 Aug;10(4):e001666. PMID: 28790153. Consevage MW et al. A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy. Hum Mol Genet. 1994 Jun;3(6):1025-6. PMID: 7848441. Gonzalez-Quereda L et al. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes (Basel). 2020 May 11;11(5):539. PMID: 32403337. Robyns T et al. Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. Eur J Med Genet. 2020 Mar;63(3):103754. PMID: 31513939. 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 08, 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.Arg719Gln (R719Q; c.2156G>A) in the MYH7 gene As of our first review in 2012, this variant had been reported in at least 11 unrelated cases of HCM with moderate segregation data in 1 family (4 individuals) and no functional studies. (Our literature search has not been updated since 2012.) Consevage et al. (1994) first reported this variant in a Hispanic family. It segregated with disease in all 4 affected family members (a child, parent, grandparent, and uncle), with the greatest separation being 2nd degree relatives. Moolman-Smook (1999) identified it in a South African patient of northern-European descent. Huang et al. (2001) identified it in a Chinese family. Van Driest et al. (2002) identified it in 2 unrelated HCM patients at the Mayo Clinic. Waldmuller et al. (2002) used this variant in developing a microarray screen for recurring HCM variants. Richard et al. (2003) identified Arg719Gln in one HCM patient recruited in France. Van Driest et al. (2004) reported a case of a patient with a double variant: Arg719Gln and Thr1513Ser (phase unknown); they also reported 2 additional, unrelated patients…but it’s unclear if these are the 2 from 2002. Ingles et al. (2005) found the variant in an Australian double heterozygote who also carried an Arg273His variant in MYBPC3. Her son inherited both variants along with the disease. Yu et al. (2005) found Arg719Gln in two unrelated Australian families. Morita et al. (2008) found it in one HCM case. Wang et al. (2008) found it in at least one Chinese HCM case. Harris et al. (2010) found it in cis with a T1513S MYH7 variant in an HCM patient and her affected mother. Garcia-Pavia et al. (2011) found it in one HCM proband in Spain. This variant is listed in ClinVar, and it is classified as pathogenic by Harvard’s Laboratory for Molecular Medicine which reports seeing it in 12 families. LMM also reports that it did segregate with disease in their internal data. Other changes at this same codon, Arg719Trp and Arg719Pro, have been associated with HCM (Harvard Sarcomere Protein Gene Mutation Database). Variation at nearby loci of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Pro710Arg, Pro710His, Arg712Leu, Gly716Ala, Gly716Arg, Arg721Lys, Arg723Cys, Arg723Gly, Arg723His, and Ala728Val (GeneDx report). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Glutamine. The Arginine at codon 719 is highly conserved across 41 vertebrate species examined (it is a Lysine in 7 species: Chicken, Tetraodon, Fugu, Stickleback, Medaka, Zebrafish, and Lamprey). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging”. The residue is in a domain that has been proposed to interact with the myosin light chains, a domain adjacent to the invariant SH1/SH2 domain (Rayment et al. 1995). In total the variant has not been seen in >60,000 published controls and publicly available population datasets. There is no variation at codon 719 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 6/16/2015). There is also no variation at this codon listed in 1000 genomes (as of 6/16/2015). The variant was not observed in published controls: Consevage et al. (1994) did not observe it in 42 controls. Moolman-Smook (1999) did not observe it in 100 controls. Huang et al. (2001) did not find it in 60 Chinese controls. Van Driest et al. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2021	Identified in multiple unrelated individuals diagnosed with HCM from various ethnic backgrounds (Consevage et al., 1994; Moolman-Smook et al., 1999; Van Driest et al., 2002; Richard et al., 2003; Van Driest et al., 2004; Ingles et al., 2005; Fokstuen et al., 2011; Kassem et al., 2013; Liu et al., 2013; Marsiglia et al., 2013; Nunez et al., 2013; Kapplinger et al., 2014; Rubattu et al., 2016; Burns et al., 2017); Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564422.4; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate reduced actin filament velocity and mouse models show pathologic remodeling in cardiac tissue (Yamashita et al., 2000; Teekakirikul et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15858117, 27483260, 27532257, 27247418, 31006259, 18411228, 12473556, 12707239, 11968089, 15358028, 16199542, 18403758, 19645038, 20811150, 20309391, 20800588, 23233322, 24510615, 23782526, 24093860, 11498078, 10521296, 23711808, 21239446, 27590665, 21310275, 28323875, 28790153, 29300372, 31513939, 32403337, 30847666, 32894683, 33673806, 7848441, 10882745) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2156G>A (p.Arg719Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:7848441; PMID:16199542; PMID:15358028; PMID:18411228; Partners LMM ClinVar SCV000059421.5; AGCMC Sydney ClinVar SCV000212634.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:7848441; Partners LMM ClinVar SCV000059421.5). 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). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2155C>T p.Arg719Trp ClinVar Variation ID 14104). 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; PP1_ Strong; PM1; PM2; PM5; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 719 of the MYH7 protein (p.Arg719Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 7848441, 15358028, 15519027, 15858117, 16199542, 18409188, 21896538, 23140321, 23711808). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14107). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 10882745). This variant disrupts the p.Arg719 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8282798, 20811150, 21310275). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2023	proposed classification - variant undergoing re-assessment, contact laboratory -

Hypertrophic cardiomyopathy 1 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 28, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.93). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15358028 , 16199542 , 18411228 , 30297972 , 7848441). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 7848441). Different missense changes at the same codon (p.Arg719Pro, p.Arg719Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014104 , VCV000217460). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1999	- -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	-	This MYH7 Arg719Gln mutation has previously been described in multiple HCM cohorts (see references). It was first reported in a Hispanic family with HCM (Consevage MW, et al., 1994) and has been detected in individuals of other ethnic backgrounds (Moolman-Smook JC, et al., 1999; Huang X, et al., 2001; Marsiglia JD, et al., 2013). This mutation has been shown to cosegregate with disease, however, disease espressivity is variable. Many reports have described the clinical characteristics of this MYH7 Arg719Gln mutation with early-onset disease (Consevage MW, et al., 1994) and/or a positive family history of sudden cardiac death events (Huang X, et al., 2001; Van Driest SL, et al., 2004; Fokstuen S, et al., 2008; Morita H, et al., 2008). This mutation occurs at a known hotspot region of the MYH7 gene and a different HCM causing mutation at this position (Arg719Trp) has been documented (Tesson F, et al., 1998; Marsiglia JD, et al., 2013). In our cohort, we have identified two HCM index cases with this Arg719Gln mutation, of which one case was identified to be a double heterozygote with another mutation in the MYBPC3 gene (Ingles J, et al., 2005). Based on literature evidence, familial segregation analysis, and absence in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), we classify this variant as "pathogenic". -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 07, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The p.R719Q pathogenic mutation (also known as c.2156G>A), located in coding exon 17 of the MYH7 gene, results from a G to A substitution at nucleotide position 2156. The arginine at codon 719 is replaced by glutamine, an amino acid with highly similar properties, and is located in the head domain. This alteration was reported to co-segregate with hypertrophic cardiomyopathy (HCM) in one family, and was reported as an apparent de novo occurrence in a proband with HCM (Consevage MW et al. Hum Mol Genet. 1994;3(6):1025-6; Garcia-Pavia P et al. Eur J Heart Fail. 2011;13(11):1193-201). This mutation has been reported in multiple HCM cohorts in unrelated individuals with HCM, some with early-onset disease or a family history of HCM and sudden death (Moolman-Smook JC et al. Am. J. Hum. Genet., 1999 Nov;65:1308-20; Huang X et al. Clin Chim Acta. 2001;310(2):131-9; Kapplinger JD et al. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Rubattu S et al. Int J Mol Sci, 2016 Jul;17; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.94	A
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.047	D
Polyphen		0.57	P
Vest4		0.79
MutPred		0.77		Gain of catalytic residue at R721 (P = 0.0028);
MVP		0.97
MPC		1.9
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs121913641; hg19: chr14-23895179; COSMIC: COSV100806984;