14-23422291-C-A

Variant names:

• chr14-23422291-C-A
• rs397516178
• NM_000257.4:c.3134G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PP1_Moderate PM2 PP3

This summary comes from the ClinGen Evidence Repository: The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). 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 hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013375/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.76
• Publications: 16 publications found

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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294572 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.
• 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 rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3134G>T	p.Arg1045Leu	missense_variant	Exon 25 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3134G>T	p.Arg1045Leu	missense_variant	Exon 24 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3134G>T	p.Arg1045Leu	missense_variant	Exon 25 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.3134G>T	p.Arg1045Leu	missense_variant	Exon 25 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.3134G>T	p.Arg1045Leu	missense_variant	Exon 24 of 39			ENSP00000519071.1
ENSG00000294572	ENST00000724465.1	n.174C>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251460 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000124 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Dec 18, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1045Leu variant in MYH7 has been identified in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives from 3 families (Cann 2017, Walsh 2017, Invitae pers. comm., GeneDx pers. comm., LMM data). It has also been identified in 1 individual with HCM who carried an additional pathogenic variant in MYH7 (LMM data). This variant has also reported by other clinical laboratories in ClinVar (Variation ID#42948) and has been identified in 0.004% (4/113744) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg1045Cys) has been identified in individuals with HCM and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Moderate, PM5_Supporting. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1045 of the MYH7 protein (p.Arg1045Leu). This variant is present in population databases (rs397516178, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42948). 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%. This variant disrupts the p.Arg1045 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 20215591, 24793961, 26914223, 27247418, 27532257). 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. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with leucine at codon 1045 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27000522, 27532257, 29764897, 33495596, 33495597; ClinVar SCV001976477.1). Several of these individuals also carried variants in other genes associated with hypertrophic cardiomyopathy (ClinVar SCV001976477.1). It has been shown that this variant segregates with disease in 6 affected individuals across 3 families (ClinVar SCV001976477.1). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 35732239). This variant has been identified in 4/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg1045Cys, is considered to be disease-causing (ClinVar variation ID: 177753), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 25, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). 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 hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PP3. -

Cardiomyopathy Pathogenic:1

Nov 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with leucine at codon 1045 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27000522, 27532257, 29764897, 33495596, 33495597; ClinVar SCV001976477.1). Several of these individuals also carried variants in other genes associated with hypertrophic cardiomyopathy (ClinVar SCV001976477.1). It has been shown that this variant segregates with disease in 6 affected individuals across 3 families (ClinVar SCV001976477.1). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 35732239). This variant has been identified in 4/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg1045Cys, is considered to be disease-causing (ClinVar variation ID: 177753), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

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

Sep 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 30, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in patients with HCM in published literature (PMID: 34503678, 27000522, 25611685, 27532257); Identified in patient with DCM and LVNC requiring heart transplant who harbored a second variant in MYH7 (PMID: 35732239); 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: 25611685, 27532257, 27247418, 34503678, 27000522, 1976477, 31447099, 34636345, 35653365, 26914223, 37652022, 34542152, 29764897, 19659763, 33495596, 33495597, 35732239) -

Cardiovascular phenotype Pathogenic:1

Feb 14, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1045L pathogenic mutation (also known as c.3134G>T), located in coding exon 23 of the MYH7 gene, results from a G to T substitution at nucleotide position 3134. The arginine at codon 1045 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in numerous hypertrophic cardiomyopathy cohorts and has been reported to segregate with disease in several families (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203; Sheikh N et al. Circulation, 2018 Sep;138:1184-1194; personal communication). 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 variant is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Oct 12, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene has been reported in at least three unrelated patients with hypertrophic cardiomyopathy (PMID 25611685, 26914223, 27247418) and is extremely rare in general population databases. A second variant in the same codon, p. Arg1045His was classified likely pathogenic by our laboratory. A third variant at this codon, p.Arg1045Cys was classified as likely pathogenic by expert panel in the Clinvar database, suggesting this arginine residue is critical for MYH7 protein function. Multiple lines of prediction algorithms support the deleterious effect of the c.3134G>T (p.Arg1045Leu) variant. Therefore, this c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.64		Loss of MoRF binding (P = 0.0262);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516178; hg19: chr14-23891500;