NM_000257.4:c.2302G>A

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 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. 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 Lovd. Synonymous variant affecting the same amino acid position (i.e. G768G) has been classified as Likely benign.

• 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:8
• Conservation: PhyloP100: 7.51

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 21 ACMG points.

• PS1: Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a region_of_interest Actin-binding (size 14) in uniprot entity MYH7_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) 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 hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated 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 [Likely_pathogenic]. Clinvar id is 164337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23425403-C-T is described in Lovd as [Pathogenic]. Variant chr14-23425403-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2302G>A	p.Gly768Arg	missense_variant	Exon 21 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2302G>A	p.Gly768Arg	missense_variant	Exon 20 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2302G>A	p.Gly768Arg	missense_variant	Exon 21 of 40	1	NM_000257.4	ENSP00000347507.3

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

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

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;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

- -

Hypertrophic cardiomyopathy Pathogenic:1

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. -

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 v4.3

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
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

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: rs727503260; hg19: chr14-23894612;