rs45516091

Positions:

• chr14-23431608-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_Moderate PM2 PP3 PP1 PM6_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.709C>T (p.Arg237Trp) variant has been identified in at least 10 individuals with DCM, 3 of whom also carried other disease-causing variants (PS4_Moderate; Hershberger 2008 PMID:19412328; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; Franaszczyk 2017 PMID:28045975; Dal Ferro 2017 PMID:28416588; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant has also been identified in 2 individuals with unspecified cardiomyopathy, 1 individual with LVNC, and 1 with ventricular tachycardia (GeneDx pers. comm.; Invitae pers. comm.). This variant has been reported as de novo in 1 individual with sudden death and suspected HCM based on autopsy (PM6_supporting; Ambry pers. comm.); however, because the reported phenotype is not specific enough, the PM6 criterion was downgraded to PM6_supporting. This variant segregated with disease in 3 affected individuals with DCM in 1 family (LMM pers. comm.). In vitro functional studies provide some evidence that this variant impacts protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Ujfalusi 2018 PMID:29666183; Liu 2018 PMID:29867217). This variant was identified in 0.0023% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. 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 likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM6_Supporting, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016662/MONDO:0005021/002

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH7 ENST00000355349.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1
• Conservation: PhyloP100: 0.295

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.709C>T	p.Arg237Trp	missense_variant	8/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.709C>T	p.Arg237Trp	missense_variant	7/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.709C>T	p.Arg237Trp	missense_variant	8/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251496 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 22, 2015	The p.Arg237Trp variant in MYH7 has been previously identified by our laboratory in 1 adult with DCM and segregated with disease in 6 affected relatives from 1 family including 1 obligate carrier and 1 individual with an enlarged LV. This v ariant has also been reported in the literature in 1 individual with DCM (Hershb erger 2008). This variant has been identified in 1/11608 of Latino chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45516091). Please note that for diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the genera l population. Computational prediction tools and conservation analysis suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, this variant meets our criteri a to be classified as pathogenic for DCM in an autosomal dominant manner (http:/ /www.partners.org/personalizedmedicince/LMM) based on segregation studies and ex tremely low frequency in controls. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jan 05, 2024	This sequence change in MYH7 is predicted to replace arginine with tryptophan at codon 237, p.(Arg237Trp). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the myosin head domain, a region (amino acids 167-931) that is defined as a mutational hotspot (PMID: 30696458). There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.005% (3/59,026 alleles) in the admixed American population, which is consistent with dilated cardiomyopathy. This variant has been reported in at least six probands with dilated cardiomyopathy (DCM) and to segregate with DCM in at least one family (PMID: 16911908, 27532257; ClinVar: SCV000059645.6, SCV000207088.1, SCV000208814.11, SCV001443153.1, SCV002073292.1). This variant has also been observed with a TTN truncating variant in an individual with DCM (PMID: 28045975). The variant alters enzyme activity in functional studies (with limited validation) by reducing protein function, which is consistent with DCM-associated pathogenic MYH7 variants (PMID: 29666183, 29867217). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.815). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PS4_Moderate, PM2_Supporting, PP1, PP3, PS3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	The c.709C>T (p.Arg237Trp) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least three individuals affected with Dilated Cardiomyopathy (DCM) (PMID:27532257, 28416588) and segregated with disease in six affected relatives in one family (internal data from a ClinVar submitter, ClinVar ID: 43098). In addition, this variant has been reported in individuals with DCM who also harbor pathogenic variants in LDB3 or TTN genes (PMID: 19412328, 28045975). This variant lies in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations, and missense variants in this region are statistically more likely to be disease-associated (PMID: 27532257, 27247418). In-silico computational prediction tools suggest that the p.Arg237Trp variant may have deleterious effect on the protein function (REVEL score: 0.815). This variant is found to be rare (3/251496; 0.001193%) in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 43098). Therefore, the c.709C>T (p.Arg237Trp) variant in the MYH7 gene is classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 29, 2014	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Apr 23, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 23, 2023	This missense variant replaces arginine with tryptophan at codon 237 in the myosin head/motor (S1) domain of the MYH7 protein. 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). Functional studies using recombinant MYH7 protein has shown that this variant may cause altered rate constants (PMID: 29666183, 29867217); the clinical relevance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: SCV000059645.6). It has been shown that this variant segregates with disease in 6 affected individuals from one family (communication with an external laboratory; ClinVar SCV000059645.6). This variant has been identified in 3/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 18, 2018	The c.709C>T (p.Arg237Trp) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least three individuals affected with Dilated Cardiomyopathy (DCM) (PMID:27532257, 28416588) and segregated with disease in six affected relatives in one family (internal data from a ClinVar submitter, ClinVar ID: 43098). In addition, this variant has been reported in individuals with DCM who also harbor pathogenic variants in LDB3 or TTN genes (PMID: 19412328, 28045975). This variant lies in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations, and missense variants in this region are statistically more likely to be disease-associated (PMID: 27532257, 27247418). In-silico computational prediction tools suggest that the p.Arg237Trp variant may have deleterious effect on the protein function (REVEL score: 0.815). This variant is found to be rare (3/251496; 0.001193%) in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 43098). Therefore, the c.709C>T (p.Arg237Trp) variant in the MYH7 gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the MYH7 protein (p.Arg237Trp). This variant is present in population databases (rs45516091, gnomAD 0.006%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19412328, 27532257, 28416588; Invitae). ClinVar contains an entry for this variant (Variation ID: 43098). 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: 29666183). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1S Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.R237W in MYH7 (NM_000257.4) has been reported previously in several individuals affected with dilated cardiomyopathy, two of whom harbored another variant in LDB3 and TTN respectively (Walsh R et al; Dal Ferro M et al; Hershberger et al; Kelly M et al). It has been submitted to ClinVar with varying interpretations of Pathogenicty: Likely Pathogenic/VUS. The submission to ClinVar by one laboratory states that the variant was detected in an affected individual and segregated in his family within affected members.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. The p.R237W variant is observed in 3/34,592 (0.0087%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The variant is predicted to be damaging by in silico predictions and the residue is weakly conserved across species. For these reasons, this variant has been classified as Likely Pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Nov 16, 2020

We observed the c.709C>T (p.R237W) variant in a 62-y.o. female proband, diagnosed with left ventricular non-compaction, arrhythmogenic right ventricular dysplasia and dilatation of cardiac chambers. The c.709C>T (p.R237W) variant is a known rare variant with frequency approx. 1.193e-5 (gnomAD). It was previously described in the patients with DCM. Its functional impact was shown in the studies of Liu et al (2018) and Ujfalusi et al (2018). Additionally, it should be noted that the p.R237W variant is a missense variant in MYH7 gene with z-score of 3.93 (gnomAD), therefore, MYH7 gene is likely to be intolerant of missense changes. In silico programs (PolyPhen2, MutationTaster, SIFT) also classify the p.R237W variant as probably pathogenic. Based on the evidence, we classify the c.709C>T (p.R237W) variant as likely pathogenic. The c.709C>T (p.R237W) variant was observed in combination with the p.Q1233* variant in MYBPC3 gene. Both variants were at heterozygous state. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2024

Identified in patients with cardiomyopathy in the published literature; several patients harbored additional cardiogenetic variants (PMID: 19412328, 24503780, 28416588, 27532257, 28045975, 37652022, 36396199); 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: 22337857, 27532257, 28045975, 23403236, 28416588, 24503780, 34542152, 31514951, 31447099, 19412328, 29300372, 37652022, 36396199) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The p.R237W variant (also known as c.709C>T) is located in exon 8 (coding exon 6) of the MYH7 gene. This alteration results from a C to T substitution at nucleotide position 709. The arginine at codon 237 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration occurred de novo in a post-mortem case tested by our laboratory reportedly with hypertrophic cardiomyopathy (Ambry internal data). In addition, this variant has been reported in individuals with familial dilated cardiomyopathy (DCM) who also carried variants in the LDB3 or TTN genes (Hershberger RE et al. Clin Transl Sci. 2008 1:21-6; Franaszczyk M et al. PLoS ONE. 2017;12(1):e0169007), and has been detected in additional DCM cohorts (Dal Ferro M et al. Heart. 2017;103(21):1704-1710; Walsh R et al. Genet Med, 2017 02;19:192-203; Gigli M et al. J Am Coll Cardiol, 2019 09;74:1480-1490). Functional studies suggest this variant may alter myosin force generation capacity; however, the physiological relevance is unclear (Ujfalusi Z et al. Biol Chem. 2018;293(23):9017-9029). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Dec 23, 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.Arg237Trp in MYH7. We classify it as a variant of uncertain significance, concluding that there is insufficient data to determine whether this variant causes cardiomyopathy. This variant has been published in two individuals with DCM and also observed by GeneDx in one DCM patient from Stanford and in another individual with cardiomyopathy. One of the published DCM cases also harbored a likely disease-causing variant in LDB3 (Hershberger et al, 2008). The other published DCM case (a Caucasian male with a family history of DCM) from the Laboratory for Molecular Medicine had multiple additional variants of unknown significance in the ACTN2, CTF1, and TTN genes (Pugh et al, 2014). The lab reports in ClinVar that it segregated with disease in 1 affected relative. LMM classifies it as a variant of unknown significance. p.Arg237Trp results in a non-conservative amino acid change with replacement of a hydrophilic Arginine with a hydrophobic Tryptophan residue at a position that is highly conserved across vertebrate species throughout evolution (it is a Cysteine in the turkey). In silico analysis (PolyPhen2) predicts this change to be probably damaging to the structure/function of the protein. SIFT predicts it to be deleterious. Variants at nearby residues (p.Leu227Val, Asn232Ser, p.Ala233Ser, p.Thr235Asn, p.Val236Ile, p.Asp239Asn, Arg243Cys, Arg243His, Phe244Leu, Lys246Gln, Phe247Leu) have been reported in association with hypertrophic cardiomyopathy or, more rarely, dilated cardiomyopathy. This variant has been seen in 1 Hispanic individual from ~60,000 total published controls and individuals from publicly available population datasets. It was not identified by Hershberger et al. in 253 control samples of varying ethnic backgrounds. The variant is not currently listed in the NHLBI Exome Sequence dataset (as of 6/10/2015), which includes ~6500 Caucasian and African-American individuals. It is not present in 1000 Genomes. The variant is listed in dbSNP (rs45516091), however the only submitted data seems to be that it was not observed in 16 Asian, 16 Hispanic, 181 Caucasian, 22 African American individuals from Corriel. Our patient’s ancestry is Hispanic. Ancestry-matched individuals can be found in greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC currently contains 5789 “Latino” individuals. There is only 1 individual in ExAc with this variant, and that person is Latino. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	0.18
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.75		Gain of catalytic residue at K234 (P = 5e-04);
MVP		0.96
MPC		2.2
ClinPred		0.99	D
GERP RS		-2.6
Varity_R		0.63
gMVP		0.99

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: rs45516091; hg19: chr14-23900817;