rs121913637

Positions:

• chr14-23425971-G-A

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PP3 PS3 PM1 PM5 PM2 PP1_Strong PS2 PS4

This summary comes from the ClinGen Evidence Repository: The c.2155C>T (p.Arg719Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; PMID:22429680; PMID:23816408; PMID:12707239; PMID:19645038; PMID:27532257; SHaRe consortium, PMID:30297972; Partners LMM ClinVar SCV000059419.5 ), including 1 de novo occurrence (PS2; 10957787). This variant was found to segregate with disease in 8 affected family members (PP1_Strong; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; SHaRe consortium, PMID:30297972). A mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:24829265). 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.2156G>A p.Arg719Gln - Variation ID 14107). 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): PS2; PS3; PS4; PP1_ Strong; PM1; PM2; PM5; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011779/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 1.19

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 23 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• PM5: 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.2155C>T	p.Arg719Trp	missense_variant	19/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2155C>T	p.Arg719Trp	missense_variant	18/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2155C>T	p.Arg719Trp	missense_variant	19/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 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: 0.00000274 AC: 4 AN: 1461500 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

Gnomad4 AFR exome AF: 0.0000299

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: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

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

Alfa AF: 0.0000617 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate increased myosin activity, reduced calcium sensitivity, and increased muscle fiber stiffness (Kohler et al., 2002; Adhikari et al., 2019); This variant is associated with the following publications: (PMID: 27247418, 16504640, 10882745, 8282798, 28166811, 28138913, 7874131, 29907873, 19651039, 9544842, 9822100, 21769673, 25346696, 20624503, 21310275, 23816408, 27532257, 29300372, 19645038, 27082122, 29497013, 29386531, 28420666, 29101517, 28296734, 24510615, 29029073, 29343710, 11904418, 24829265, 30775854, 31737537, 31213605, 32612965, 33673806, 32746448, 32894683) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 10, 2013	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. This variant has been reported in at least 17 unrelated individuals with HCM (including the two patients in our center) with strong segregation data. Of note, there is data suggesting this variant is associated with a more severe phenotype and high penetrance. In our center we have seen the variant in two patients: a woman diagnosed with HCM at 14 years of age and a man diagnosed with HCM at 29 years of age. The variant was first reported by Greve et al (1994). Unfortunately that report is not available, though the title suggests the variant was de novo. The same group reported four unrelated families with p.Arg719Trp (Anan et al 1994). The authors note that all individuals with HCM in these three kindreds carried the variant. They don’t specify how many individuals were genotyped, though it seems that at least 9 were tested from one family and at least 12 in another, providing very strong segregation data. Jeschke et al (1998) reported a case of childhood-onset HCM and arrest with p.Arg719Trp, which arose de novo, and an additional MYH7 variant inherited from the unaffected mother (p.Met349Thr) (also reported in Dohlemann et al 2000). Paternity was confirmed. While maternity was not formally assesed, it is highly likely to be as reported given maternal inheritance of p.Met349Thr. Jaaskelainen et al (1998) observed the variant in three affected family members from their Finnish cohort. The proband’s mother did have some hypertrophy but was negative for the variant. Poutanen et al (2006) reported two children from the same family with p.Arg719Trp who both had wall thickness at the upper limits of normal, diastolic dysfunction, and pathological Q waves. Richard et al (2003) observed the variant in one individual in their French HCM cohort. Erdmann et al (2003) reported the variant segregating with HCM in two affected members of one family from their German cohort. Frisso et al (2009) observed the variant in three unrelated individuals from their Italian cohort. Santos et al (2012) observed this variant in one individual in their Portuguese cohort. GeneDx reports that p.Arg719Trp was observed in multiple additional unrelated individuals tested for HCM. This is a non-conservative amino acid change with a polar, positive Arginine replaced with a non polar, neutral Tryptophan. Mutationtaster and PolyPhen2 both predict the variant to be damaging. Arginine is conserved at this position across mammals. Other variants at the same codon (p.Arg719Gln (which we consider likely disease causing), p.Arg719Pro) and nearby codons (p.Gly716Arg, p.Arg721Lys, p.Arg712Leu, p.Gly716Arg, p.Arg723Cys, p.Arg723Gly, and p.Ala728Val have been reported in association with HCM (Harvard Sarcomere Protein Gene Mutation Database). Seebohm B et al (2009) demonstrated that the variant could interfere with myosin cross bridge function during contraction. Kohler et al (2002) observed an increase in force generation and fiber stiffness of muscle fibers with p.Arg719Trp and suggested that the cross-bridges were more resistant to elastic distortion. Anan et al (1994) suggested that this variant may be correlated with a particularly severe phenotype since the four families they studied with the variant had a particularly high frequency of disease-related deaths. Many of the initial genotype-phenotype correlations based on a handful of cases have since been called into question by the observation of mild disease in other families with the same variant, suggesting the initial observations may have been due to ascertainment bias. However, a recent paper from the same group found significantly earlier age of onset and age of first cardiac event in carriers of p. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 18, 2017	- -

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 719 of the MYH7 protein (p.Arg719Trp). This variant is present in population databases (rs121913637, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8282798, 9544842, 9822100, 11904418, 12707239, 16504640, 19651039, 21769673). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14104). 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, 11904418, 19651039). 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2019	The p.Arg719Trp variant in MYH7 has been identified in >30 individuals with HCM (Treger 1965, Hejtmancik 1991, Anan 1994, Greve 1994, Jeschke 1998, Jääskeläinen 1998, Richard 2003, Jääskeläinen 2004, Poutanen 2006, Wang 2009, Santos 2012, Meyer 2013, Walsh 2017, Kelly 2018). In addition, it segregated with disease in >20 affected relatives from multiple families (Hejtmancik 1991, Anan 1994, Wang 2009, Guo 2017, LMM data) and was reported to have occurred de novo in 2 individuals (Greve 1994, Jeschke 1998). It has also been identified in 1/15430 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Yamashita 2000, Kohler 2002, Seebohm 2009, Tripathi 2011). Other variants involving this codon, p.Arg719Gln and p.Arg719Pro, have also been associated with HCM. 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). This variant was classified as pathogenic on 12/15/16 by the ClinGen-approved Inherited Cardiomyopathy Expert Panel (Variation ID 14104). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS2, PS3_Moderate, PM1, PM2, PM5, PP3. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Sep 27, 2018	This variant has been identified in 3 HCM probands by our research program. For further information please feel free to contact us. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2155C>T (p.Arg719Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; PMID:22429680; PMID:23816408; PMID:12707239; PMID:19645038; PMID:27532257; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059419.5 ), including 1 de novo occurrence (PS2; 10957787). This variant was found to segregate with disease in 8 affected family members (PP1_Strong; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; SHaRe consortium, PMID: 30297972). A mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:24829265). 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.2156G>A p.Arg719Gln - Variation ID 14107). 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): PS2; PS3; PS4; PP1_ Strong; PM1; PM2; PM5; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces arginine with tryptophan at codon 719 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 deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant affects MYH7 protein function by causing an increase in force generation and stiffness of muscle fibers (PMID: 11904418, 19651039, 21769673). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 8282798, 15000344, 16504640, 20378854, 23816408, 25239116, 27532257, 30297972, 30775854, 32612965) and has been observed as de novo occurrence in some affected individuals (PMID: 9544842, 10957787). This variant has been shown to segregate with disease in multiple families (PMID: 9829907, 16504640, 19645038, 25558701, 32612965). A different missense variant at the same codon, p.Arg719Gln, is a well documented pathogenic mutation (ClinVar variation ID: 14107). This variant has been identified in 1/31394 chromosomes 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:3

Pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 16, 2019	- -

Dilated cardiomyopathy 1S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KTest Genetics, KTest

-

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 27, 2023

- -

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

Nov 15, 2021

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 24, 2019

Variant summary: MYH7 c.2155C>T (p.Arg719Trp) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251466 control chromosomes (gnomAD). c.2155C>T has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy, with evidence of co-segregation with disease in multiple families and an observed association with high risk for premature death (e.g. Abchee_1997, Anan_1994, Kelly_2018, Poutanen_2006, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Nonrandom mutation cluster analysis revealed that rare MYH7 missense variants located between residues 181 and 937 have a statistically increased likelihood of being disease-associated (Walsh_2017). Experimental evidence evaluating an impact on protein function demonstrated that the variant significantly increased stiffness and force generation of the individual mutated myosin heads, resulting in reduced elastic distortion of the mutated myosin heads during isometric force generation (Seebohm_2009). Eight ClinVar submitters including an expert panel (ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

The p.R719W pathogenic mutation (also known as c.2155C>T), located in coding exon 17 of the MYH7 gene, results from a C to T substitution at nucleotide position 2155. The arginine at codon 719 is replaced by tryptophan, 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 alteration has been described in a number of hypertrophic cardiomyopathy (HCM) cohorts, often characterized by significant hypertrophy and an early age of onset, and has been shown to segregate with disease in several families (Anan et al. J Clin Invest. 1994; 93:280; Zhao Y et al. Int. J. Mol. Med., 2016 Jun;37:1511-20; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10:[Epub ahead of print]; Zhang L et al. Front Pediatr, 2020 Jun;8:312). Additionally, this alteration was confirmed to be a de novo occurrence in a child with HCM (Jeschke B et al. Hum Genet. 1998;102:299-304). In functional in vitro analyses, this alteration has demonstrated increased muscle fiber stiffness and generation of force resulting from reduced elastic distortion of the myosin head during contraction, thus suggesting disruption of myosin cross-bridge function (Seebohm B et al. Biophys J. 2009;97:806-24). 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	Pathogenic	0.88
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.99	A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.80		Gain of catalytic residue at R721 (P = 0.0019);
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.72
gMVP		0.98

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: rs121913637; hg19: chr14-23895180; COSMIC: COSV62523084;