rs267606911

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1491G>T(p.Glu497Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,094 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E497G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.72

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23428588-T-C is described in Lovd as [Likely_pathogenic].

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 14-23428587-C-A is Pathogenic according to our data. Variant chr14-23428587-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23428587-C-A is described in Lovd as [Pathogenic]. Variant chr14-23428587-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.1491G>T	p.Glu497Asp	missense_variant	15/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.1491G>T	p.Glu497Asp	missense_variant	14/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.1491G>T	p.Glu497Asp	missense_variant	15/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000230

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

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 24, 2021	PS4, PM2_supporting, PM1, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	Reported in individuals with sub-clinical cardiomyopathy (Captur et al., 2014; Ho et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional analysis of the Drosophila myosin heavy chain ortholog and molecular modeling of human beta-cardiac myosin suggest that charge reversal of E497 disrupts a salt bridge with R712, which may decrease ATPase activity and actin sliding velocity (Kronert et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18555187, 21958740, 24510615, 25543971, 25351510, 27247418, 27532257, 23549607, 26246073, 24793961, 16267253, 25558701, 28193612, 32894683, 29300372, 33605878, 34542152, 29121657, 26446785, 25228707, 31447099) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 08, 2014	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.Glu497Asp (c.1419G>T) in MYH7. The results have been re-reviewed multiple times, most recently on August 27th, 2014. Additional data further supporting pathogenicity was available. Given the strong case data, the segregation data, and the absence in the general population we consider this variant likely disease causing. To the best of our knowledge this variant has been seen in at least 9, but possibly 14 unrelated families with HCM (not including this patient's family). There may be overlap between some of the published cases and cases in our center and in the genetic testing labs databases. We have seen this variant in three families with HCM in our center. The variant was reported in two members of one family with HCM studied by the Seidman group (Arad et al 2005).The proband in this family had apical hypertrophy while the other family member with this variant had massive concentric hypertrophy, syncope, and an ICD, along with comorbid coronary artery disease. For one of the family’s in our center, there is moderate co-segregation data to support the pathogenicity of this variant in that four individuals with HCM either tested positive for this variant or can be inferred to carry it based on pedigree analysis. However, we do not have confirmation of either phenotype or genotype on anyone in this family. The testing was reportedly done as part of a research endeavor. Of note, this case may overlap with the one reported by the Seidman group (Arad et al 2005). We also have segregation data in another family with both the proband and his affected mother having the variant. Per their ClinVar submission(SCV000059378), LMM has seen this variant in 5 probands with HCM. In one of those families another affected individual also had the variant. They classify this as likely pathogenic. Ackerman's group observed the variant in two unrelated patients with HCM in their Mayo cohort who underwent analysis in their local lab (Bos et al 2014). A polar, neutral Glutamate is substituted with a polar, neutral Asparagine therefore this variant change does not affect the net charge. The Glutamate at codon 497 is completely conserved across species as are the neighboring amino acids. In silico analysis with Polyphen-2 predicts this variant to be probably damaging. Per the LMM ClinVar submission, the variant was predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clinical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Mutation Taster predicts this variant to be disease-causing. Other variants in nearby codons have been reported in association with cardiomyopathy including p.Met493Leu, p.Met493Lys, p.Glu299Lys, p.Glu500Ala, p.Tyr501His, and p.Tyr501Cys. In total the variant has not been seen in ~6,800 published controls and individuals from publicly available population datasets. There is no variation at codon 497 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/8/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/8/13). The variant was not observed in the following published control samples: Arad et al. did not find this variant in 100 presumed normal control individuals. Unfortunately we don’t have control data from any of the testing laboratories. Bos et al did not observe the variant in 200 ostensibly healthy controls." -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 497 of the MYH7 protein (p.Glu497Asp). This variant is present in population databases (rs267606911, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16267253, 23549607, 24510615). ClinVar contains an entry for this variant (Variation ID: 14124). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 21310275, 26446785). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Glu497Asp variant in MYH7 has been reported in >=6 individuals with HCM and segregated with disease in 3 affected relatives from 2 families (Arad 2005, Ho 2013, Kapplinger 2014, Homburger 2016, LMM data). This variant has also been reported by other clinical laboratories in in ClinVar (Variation ID 14124) and has been identified in 2/9850 Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs267606911). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Glutamic acid (Glu) at position 497 is highly conserved in mammals and across evolutionarily distant species and the change to aspartic acid (Asp) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, the p.Glu497Asp variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu497Asp variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PP1_Supporting, PP3, PM1. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces glutamic acid with aspartic acid at codon 497 in the myosin head/motor domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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 hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 16267253, 21958740, 23549607, 24793961, 25351510, 25558701, 25611685, 27247418, 27532257, 29121657, 32894683, 33495597, 33764162, 34556856, 35470680). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 16267253). This variant has been identified in 2/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This missense variant replaces glutamic acid with aspartic acid at codon 497 in the myosin head/motor domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. 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 hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 16267253, 21958740, 23549607, 24793961, 25351510, 25558701, 25611685, 27247418, 27532257, 29121657, 32894683, 33495597, 33764162, 34556856, 35470680). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 16267253). This variant has been identified in 2/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 01, 2023	- -

Dilated cardiomyopathy 1S

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Jan 01, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

The p.E497D pathogenic mutation (also known as c.1491G>T), located in coding exon 13 of the MYH7 gene, results from a G to T substitution at nucleotide position 1491. The glutamic acid at codon 497 is replaced by aspartic acid, an amino acid with highly similar 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 identified in numerous unrelated patients with hypertrophic cardiomyopathy and has been reported to co-segregate with disease in one small family (Arad M et al. Circulation. 2005;112(18):2805-11; Maron BJ et al. Am J Cardiol. 2011;108(12):1783-7; Arad M et al. Isr Med Assoc J. 2014;16(11):707-13; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Walsh R et al. Genet. Med. 2017;19:192-203; Mattivi CL et al. Circ Genom Precis Med. 2020 10;13(5):453-459; Puckelwartz MJ et a. J Am Heart Assoc. 2021 04;10(7):e019944; Ambry internal data). Functional studies of the orthologous residue in a transgenic Drosophila model, coupled with molecular modeling of human beta-cardiac myosin, demonstrated that E497 is involved in charge-dependent interactions between the relay helix and the converter domain. Disruption of this interaction by either charge reversal or introduction of a sterically smaller amino acid obviate this interaction, resulting in reduced ATPase activity and actin sliding velocity (Kronert WA et al. J. Biol. Chem., 2015 Dec;290:29270-80). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.51

Vest4

0.95

MutPred

0.83

Gain of catalytic residue at H492 (P = 0.0343);

MVP

0.92

MPC

2.0

ClinPred

0.98

GERP RS

3.6

Varity_R

0.84

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over