NM_000257.4:c.3236G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2PP3

The NM_000257.4(MYH7):c.3236G>A(p.Arg1079Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,834 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1079W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.185

Publications

8 publications found

Variant links:

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

MYH7 links:

ENSG00000294572 (HGNC:):

ENSG00000294572 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.3236G>A	p.Arg1079Gln	missense_variant	Exon 25 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 link	c.3236G>A	p.Arg1079Gln	missense_variant	Exon 24 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYH7	ENST00000355349.4 link	c.3236G>A	p.Arg1079Gln	missense_variant	Exon 25 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1 link	c.3236G>A	p.Arg1079Gln	missense_variant	Exon 25 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.3236G>A	p.Arg1079Gln	missense_variant	Exon 24 of 39			ENSP00000519071.1
ENSG00000294572	ENST00000724465.1 link	n.104-32C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251434

AF XY:

0.00

show subpopulations

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460746

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4874

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1112006

Other (OTH)

AF:

0.0000498

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000359

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:3

Nov 08, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 1079 of the MYH7 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27600940, 27532257, 33495597, 38489124), dilated cardiomyopathy (PMID: 21750094), or systemic amyloidosis with cardiac involvement (PMID: 24749114). This variant has also been reported in two families with hypertrophic cardiomyopathy, including three affected carriers and three unaffected carriers (PMID: 20359594, 28687478, 28790153). This variant has been identified in 2/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 1079 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27600940, 27532257, 33495597), dilated cardiomyopathy (PMID: 21750094), or systemic amyloidosis with a cardiac involvement (PMID: 24749114). This variant has also been reported in two families with hypertrophic cardiomyopathy, including three affected carriers and three unaffected carriers (PMID: 20359594, 28687478, 28790153). This variant has been identified in 2/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Jul 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg1079Gln variant in MYH7 has been identified in 3 individuals with cardiomyopathy (1 with DCM and 2 with HCM) and segregated with disease in one affected family member (WaldmÃ¼ller 2011, Cecconi 2016, LMM data). In addition, this variant was identified by our laboratory in 1 individual with HCM and 1 affected family member, who both also carried a pathogenic variant in MYBPC3. This variant has been identified in 2/129124 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID:177826). Computational prediction tools and conservation analysis suggest that the p.Arg1079Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg1079Gln variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, BP4. -

Congenital myopathy with fiber type disproportion

Uncertain:1

Sep 22, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2. -

Hypertrophic cardiomyopathy

Uncertain:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1079 of the MYH7 protein (p.Arg1079Gln). This variant is present in population databases (rs727504342, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20359594, 21750094, 24749114, 25611685, 27532257, 27600940, 28687478, 28790153; internal data). ClinVar contains an entry for this variant (Variation ID: 177826). 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 not expected to disrupt MYH7 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Apr 10, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

This MYH7 Arg1079Gln variant is a rare occurrence in the general population; it is not observed in the 1000 genomes project (http://www.1000genomes.org/), and is a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.000008, http://exac.broadinstitute.org/). We have identified the MYH7 Arg1079Gln variant in an HCM proband where two additional MYBPC3 variants have also been observed in the family (Girolami F, et al., 2010). One of the additional variants (MYBPC3 Gln969Ter) is well described as disease-causing. Segregation analysis showed this MYH7 Arg1079Gln variant to be present in one other affected family member (who also carries the disease causative MYBPC3 Gln969Ter variant). The MYH7 Arg1079Gln has been identified in a general population (Bick AG, et al., 2012) and 2 HCM probands (Alfares AA et al., 2015; Cecconi M et al., 2016), no further evidence is provided in these studies to support a pathogenic role. This variant has also been identified in one DCM patient (WaldmÃ¼ller S, et al., 2011) and double heterozygous amyloidosis with HCM case (Ebrille E, et al., 2013). Predictions from in silico tools are contradictory with SIFT and MutationTaster predicting the amino acid substitution to be "deleterious" and "disease-causing". PolyPhen-2 predicts the impact of this variant to be "benign" (note: no prediction is made by PolyPhen-HCM). Due to limited segregation analysis due to small number of informative individuals, and co-occurrence with a MYBPC3 variant that explains the disease phenotype, we classify this MYH7 Arg1079Gln variant as one of "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostCm

Benign

0.029

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.23

PhyloP100

0.18

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.45

Sift

Benign

0.031

Sift4G

Benign

0.87

Polyphen

0.12

Vest4

0.75

MutPred

0.76

Gain of ubiquitination at K1083 (P = 0.0446);

MVP

0.81

MPC

0.44

ClinPred

0.70

GERP RS

4.9

Varity_R

0.12

gMVP

0.76

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over