14-23425403-C-T

Variant names:

• chr14-23425403-C-T
• rs727503260
• NM_000257.4:c.2302G>A

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):​c.2302G>A​(p.Gly768Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.51
• Publications: 24 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

ACMG classification

Our verdict: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 14-23425403-C-T is Pathogenic according to our data. Variant chr14-23425403-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 164337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2302G>A	p.Gly768Arg	missense	Exon 21 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.2302G>A	p.Gly768Arg	missense	Exon 20 of 39	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.2302G>A	p.Gly768Arg	missense	Exon 21 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.2302G>A	p.Gly768Arg	missense	Exon 21 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.2302G>A	p.Gly768Arg	missense	Exon 20 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Found to segregate with HCM in two unrelated families referred for genetic testing at GeneDx and reported to segregate with an HCM or RCM phenotype with the age of onset ranging from infancy to adulthood in the published literature (Hinton et al., 2010); 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: 23054336, 25524337, 34057638, 33429969, 31324451, 31737537, 25935763, 17125710, 20738943, 22260945, 23690394, 23549607, 18076673, 22555271, 20031602, 27247418, 20624503, 27600940, 28606303, 27532257, 28831623, 30165862, 30745532, 32013205, 20394946, 27535533, 12707239, 33906374, 33658374, 29300372)

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 18, 2012

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.Gly768Arg (c.2302 G>A) in the MYH7 gene (NM_000257.2). The variant has been seen in at least 7 unrelated cases of familial cardiomyopathy (not including this patient's family). There is strong segregation data in one family. The Seidmans' online database notes that in 2001 they observed the variant in two affected members of a family with HCM (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_Gly768Arg.html). They also note a "direct submission" to them by Gruver et al 2001, with no details on phenotype, ancestry, or segregation. The Seidmans' family is presumably the same family they include in later publications (Ho et al 2002, Valente et al 2013). Richard et al (2003) observed the variant in one of 197 unrelated HCM patients from their French cohort who had sequencing of 9 sarcomere genes. They note most patients were of European origin. Segregation data was not provided. Millat et al (2010) observed the variant in one of 192 unrelated French HCM patients. This appears to be a distinct cohort from that studied by Richard et al (the authors do not overlap and Millat et al reference Richard et al as if it was an independent study). No ancestry or segregation data were provided. Stephanie Ware's group reported a family with both HCM and restrictive cardiomyopathy with this variant (Ware et al 2008 and Hinton et al 2010). Affected first cousins both carried the variant. The male proband had infantile onset restrictive cardiomyopathy and was transplanted soon after diagnosis. The proband's aunt had HCM and had a baby with in utero onset of HCM who died on the first day of life and had sequencing of 8 sarcomere genes, which revealed on p.Gly768Arg. This appears to be the same case later reported by this group in a study on restrictive cardiomyopathy and conduction system disease (Walsh et al 2012). Interestingly, the same group also reported what appear to be two additional unrelated cases of HCM with this variant in a series of patients with pediatric cardiomyopathy who underwent genetic evaluation (Kindel et al 2012). One patient had HCM, presented at 10yo and had genetic testing at 14yo and had a family hsitory of cardiomyopathy and sudden death. The other presented at 2yo and had genetic tesitng at 3yo. Laredo et al (2006) observed the variant in one of 128 HCM patients in their Spanish cohort. I found a poster online from the same group that presumably describes the same case(Garcia-Giustiniani et al 2014, European Society of Cardiology http://spo.escardio.org/eslides/view.aspx?eevtid=54&fp=P4868). In the 2006 paper they report on a single affected family member with the variant, however in the 2014 poster they note there were six family members who have HCM and carry the variant. It is not currently in ClinVar (July 9th, 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.992). This is a non-conservative amino acid change with a Grantham score of 125. The glycine at codon 768 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Val763Gly, Phe764Leu, Phe764Tyr, Lys766Asn, Glu774Val, Asp778Gly, Asp778Val, Asp778Glu (in HGMD, per GeneDx report; Seidmans' database http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_mutations_TOC.html)). In total the variant has not been seen in ~6600 published controls and individuals from publicly available population datasets. There is no variation at codon 768 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (

Hypertrophic cardiomyopathy Pathogenic:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 768 of the MYH7 protein (p.Gly768Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (PMID: 12707239, 18076673, 20394946, 20800588, 22260945, 25935763; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164337). 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 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.

Jan 21, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy Pathogenic:1

Sep 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly768Arg variant in MYH7 has been reported in 13 individuals with HCM, HC M with RCM, HCM with LVNC, or RCM, and segregated with disease in 5 affected rel atives from 3 families (Richard 2003, Laredo 2006, Ware 2008, Hinton 2010, Ho 20 13, Walsh 2014, Coppini 2014, Garcia-Giustiniani 2015, LMM data). It has not bee n identified in large population studies. Glycine (Gly) at position 768 is highl y conserved in mammals and across evolutionarily distant species and the change to arginine (Arg) was predicted to be pathogenic using a computational tool clin ically validated by our laboratory. This tool's pathogenic prediction is estimat ed to be correct 94% of the time (Jordan 2011). In summary, this variant meets c riteria to be classified as pathogenic for cardiomyopathy in an autosomal domina nt manner based upon prevalence in affected probands, segregation with disease, predicted functional impact, and extremely low frequency in the general populati on.

Cardiomyopathy Pathogenic:1

Nov 25, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Jul 07, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.2302G>A (p.Gly768Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251408 control chromosomes. c.2302G>A has been observed in multiple related individual(s) affected with Hypertrophic Cardiomyopathy (Wang_2019), segregating with disease. These data indicate that the variant is likely to be associated with disease. A different variant resulting in the same amino acid consequence has been classified as likely pathogenic/pathogenic by our lab (c.2302G>C), supporting the pathogenicity of this variant. The following publication has been ascertained in the context of this evaluation (PMID: 30745532). ClinVar contains an entry for this variant (Variation ID: 164337). Based on the evidence outlined above, the variant was classified as pathogenic.

Cardiovascular phenotype Pathogenic:1

May 14, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G768R pathogenic mutation (also known as c.2302G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2302. The glycine at codon 768 is replaced by arginine, 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 reported in multiple individuals, including a pair of monozygotic twins, with hypertrophic cardiomyopathy (HCM), and once as a de novo occurrence in an individual with restrictive cardiomyopathy (RCM) (Ho CY et al. Circ Cardiovasc Imaging, 2013 May;6:415-22; García-Giustiniani D et al. Heart, 2015 Jul;101:1047-53; Walsh R et al. Genet. Med., 2017 02;19:192-203; Wang J et al. Int Heart J, 2019 Mar;60:477-481; Franaszczyk M et al. J Clin Med, 2020 Jan;9). In addition, a different alteration located at the same position, resulting in the same protein change, c.2302G>C (p.G768R), has been reported in individuals with HCM and RCM (Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24; Ware SM et al. Clin. Genet., 2008 Feb;73:165-70; Hinton RB et al. J. Pediatr., 2010 Jul;157:164-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Hypertrophic cardiomyopathy 1 Pathogenic:1

Aug 01, 2017

Phosphorus, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.80		Gain of catalytic residue at K766 (P = 0.0045)
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.87
gMVP		0.99
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: rs727503260; hg19: chr14-23894612;