rs727504273

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP2PP3_ModeratePP5

The NM_000257.4(MYH7):c.619A>C(p.Lys207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,128 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K207K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 3.12

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000257.4

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, 0.91

PP5

Variant 14-23431781-T-G is Pathogenic according to our data. Variant chr14-23431781-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177674.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.619A>C	p.Lys207Gln	missense_variant	Exon 7 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 link	c.619A>C	p.Lys207Gln	missense_variant	Exon 6 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYH7	ENST00000355349.4 link	c.619A>C	p.Lys207Gln	missense_variant	Exon 7 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1 link	c.619A>C	p.Lys207Gln	missense_variant	Exon 7 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.619A>C	p.Lys207Gln	missense_variant	Exon 6 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

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

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

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

The c.619A>C (p.Lys207Gln) variant in the MYH7 gene has been identified in at least five individuals with Hypertrophic Cardiomyopathy (HCM) (PMID: 24793961, 27247418, 27532257, 25611685, 32894683). This variant has also been reported in homozygous status in a patient diagnosed at 47 years old with HCM that later seemed to transition to dilated cardiomyopathy at 64 years old. His sibling (80 years old) who is heterozygous for this variant was also diagnosed with HCM, while his three children (age range 40-46 years old) and three grandchildren (age range 3-15 years old) who were heterozygous for this variant were asymptomatic. Five of these heterozygous individuals have a resting sinus bradycardia, suggesting an alternative phenotypic expression (PMID: 12820698, 15528230). This variant is located 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). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.801). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 177674). Therefore, the c.619A>C (p.Lys207Gln) variant in the MYH7 gene is classified as likely pathogenic. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the MYH7 protein (p.Lys207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in the heterozygous and homozygous state in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 15528230, 27247418, 27532257, 32894683; internal data). ClinVar contains an entry for this variant (Variation ID: 177674). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 22, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 25, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy

Pathogenic:2

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 lysine with glutamine at codon 207 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with affected with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have 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 individuals affected with hypertrophic cardiomyopathy (PMID: 12820698, 15528230, 24793961, 27247418, 27532257, 30297972, 32894683; ClinVar SCV002659342.3, SCV000284290.7), including one individual in homozygous state with disease onset at 47 years old. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 10, 2021

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Oct 22, 2018

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYH7 c.619A>C (p.Lys207Gln) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) and is found in a surface loop that spans the entrance to the ATP-binding pocket (Alpert 2005). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246666 control chromosomes (gnomAD and publication data). c.619A>C has been reported in the literature in a family with a homozygous individual affected with Hypertrophic Cardiomyopathy (HCM) that later seemed to transition into Dilated Cardiomyopathy (DCM); although the variant was found in several family members in heterozygosity, only one of them was affected by HCM (Mohiddin 2003, Alpert 2005). The variant was also reported to be found in HCM patient cohorts in heterozygous state (Bos 2014, Homburger 2016, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, characterizing skeletal muscle myosin from biceps muscles of the homozygous patient, however, this study does not allow convincing conclusions about the variant effect (Alpert 2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified

Uncertain:1

Jul 24, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

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.Lys207Gln (c.619 A>C) in MYH7 (NM_000257.2) We have seen this in a patient with early onset HCM, severe LVH, who also carries p.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) (phase not known). As reviewed below, we classify both of these variants as variants of uncertain significance, probably disease causing. They are good candidates, either individually or in combination, for the cause of his cardiomyopathy, however we cannot currently conclude with sufficient confidence that they are in fact the causative variants. The variant has been seen in at least two unrelated cases of HCM (not including this patient's family). Mohiddin et al (2003) reported a patient with HCM who was homozygous for this variant. The patient was from an NIH cohort of 100 HCM patients who had analysis of just MYH7. HCM was diagnosed at 47 years of age and at 64yo the maximal wall thickness was 2.1 cm, at the apex. History included syncope, appropriate shocks from his ICD, chronic atrial fibrillation, eventual left ventricular dilatation and heart failure class III symptoms. A sibling was a heterozygote and got diagnosed with HCM at 80yo with a thickness of 3.5 cm. Three children in their 40s were heterozygotes and had normal echos. Three grandchildren <16 yo Were also heterozygotes and had normal echos. Several heterozygotes had resting sinus bradycardia. Ancestry was not reported. Consanguinity was denied and haplotype analysis was not reported. The same case was included in a later publication by this group (Alpert et al 2005). Dr. Ackerman's group reported the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo. We have not seen this variant before. It is not currently listed in ClinVar (as of July 3rd, 2014). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.551). The lysine at codon 207 is conserved across all mammalian cardiac myosins, regardless of isoform (Alper et al 2002). Other variants have been reported in association with disease at nearby codons (Ala199Val, Ala200Thr, Ile201Thr, Arg204His, Ser205Cys, Q209E, Pro211Leu, Gly214Asp, Leu216Val per GeneDx report, referencing HGMD). In total the variant has not been seen in 6800 published controls and individuals from publicly available population datasets. There is no variation at codon 207 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). There is also no variation at this codon listed in dbSNP (as of July 3rd, 2014). The variant was not observed in the following published control samples: 100 (Mohiddin et al 2003), 200 (Bos et al 2014). -

not provided

Uncertain:1

Jan 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant has been reported in association with HCM in one large family with a proband homozygous for the variant. The variant segregated with HCM in one family member (PMID: 12820698;15528230); Identified in the heterozygous state in other unrelated individuals with diagnosis of HCM in the published literature (PMID: 27532257; 27247418) and independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy at GeneDx, but segregation data is limited or absent at this time.; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18391120, 21310275, 27247418, 28420666, 20298698, 12820698, 15528230, 37652022, 32894683, 27532257, 18761664, 29300372) -

Cardiovascular phenotype

Uncertain:1

Aug 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K207Q variant (also known as c.619A>C), located in coding exon 5 of the MYH7 gene, results from an A to C substitution at nucleotide position 619. The lysine at codon 207 is replaced by glutamine, an amino acid with similar properties. This alteration was reported in the homozygous state in an individual with apical hypertrophic cardiomyopathy (HCM), and in the heterozygous state in multiple family members, only one of whom also had HCM (Mohiddin SA et al. Genet. Test., 2003;7:21-7; Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol., 2005 Mar;288:H1097-102). This alteration has also been reported in other HCM cohorts, though clinical details were limited (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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 amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

CardioboostCm

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

Eigen

Benign

0.12

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.94

PhyloP100

3.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.80

Sift

Uncertain

0.023

Sift4G

Benign

0.082

Polyphen

0.75

Vest4

0.72

MutPred

0.71

Loss of ubiquitination at K207 (P = 0.0039);

MVP

0.96

MPC

2.2

ClinPred

0.82

GERP RS

3.1

Varity_R

0.44

gMVP

0.86

Mutation Taster

=20/80

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over