rs121913652

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_000257.4(MYH7):c.5647G>A(p.Glu1883Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. E1883Q) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:6

Conservation

PhyloP100: 7.78

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5647G>A	p.Glu1883Lys	missense_variant	38/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5647G>A	p.Glu1883Lys	missense_variant	37/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5647G>A	p.Glu1883Lys	missense_variant	38/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 13, 2013	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.Glu1883Lys (c.5647G>A). To the best of our knowledge there are no reports of individuals heterozygous for the variant that carry an HCM diagnosis (as of May 27th, 2015). This variant has been reported in an individual with a myosin storage myopathy and cardiomyopathy (Tajsharghi et al 2007). His parents were second cousins and thus autosomal recessive inheritance was assumed. The patient was found to be homozygous for the variant. He presented at age 44 with symptoms consistent with myosin storage myopathy, biventricular hypertrophy and heart failure. The patient had 2 affected siblings who were not genotyped. They died at ages 57 and 32. Both siblings had skeletal myopathy and died due to heart failure. The parents (presumed heterozygotes) and one other sibling (not genotyped) were reportedly normal though it is unclear if they ever had echocardiograms and the father apparently died of a stroke in his 50s. In their ClinVar entry, LMM notes "some suspension that this variant does not be the cause of disease in this family. First, homozygous mutations in MYH7 would be expected to cause an early onset of disease, which was not observed in that individual. Second, that individual is from an unknown ethnicity and the MYH7 variant maybe a common benign variant in that population. Third, individuals from a consanguineous mating carry many homozygous variants suggesting that that individual could have other variants that are also contributing to disease." The variant is listed in ClinVar with both submitting labs, GeneDx and LMM, classifying it as a variant of uncertain significance (as of May 26th, 2015). Armel et al (2009) studied the functional impact of the variant and found that the variant protein had a reduced ability to assemble properly and the paracrystals formed were degraded by proteolysis more readily (note they refer to the variant as p.Glu1886Lys). Nearly all other cases of myosin storage myopathy reported to date are autosomal dominant. This is a non conservative amino acid change with a negatively charged Glutamic Acid replaced with a positively charged Lysine. The variant is located in the rod region of the MYH7 gene, which is involved in sarcomere filament assembly. Other variants in the same domain (p.Arg1845Trp, p.Glu1886Lys) have been reported with skeletal myopathy and hypertrophic cardiomyopathy, respectively (Tajsharghi et al 2003; Armel et al 2009). In silico analysis with Polyphen predicts this variant to be probably damaging with a score of 0.998, Mutation Taster predicts this variant to be disease causing. In total the variant has not been seen in ~6,700 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 1883 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 6/20/13). Note that this dataset does not match the patient's ancestry. This variant was not detected in 200 presumably healthy individuals of Caucasian or African American descent who were tested at GeneDx. Tajsharghi et al (2007) did not report control data. There is also no variation at this codon listed in 1000 genomes (as of 6/20/13). This variant is listed in dbSNP (rs121913652) and is classified as an HGMD_mutation coding sequence variant. HGMD references Tajsharghi 2007. It is not present in ExAC, which currently has variant cals on ~60,500 individuals (May 27th, 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2014	The Glu1883Lys variant in MYH7 has been reported in homozygosity in 1 individual from a consanguineous mating with myosin storage myopathy, HCM and a family his tory consistent with recessive inheritance (Tajsharghi 2007). However, there is some suspension that this variant does not be the cause of disease in this famil y. First, homozygous mutations in MYH7 would be expected to cause an early onset of disease, which was not observed in that individual. Second, that individual is from an unknown ethnicity and the MYH7 variant maybe a common benign variant in that population. Third, individuals from a consanguineous mating carry many h omozygous variants suggesting that that individual could have other variants tha t are also contributing to disease. This variant was absent from large populatio n studies, though it has been reported in dbSNP without frequency information (d bSNP rs121913652). Glutamic acid (Glu) at position 1883 is highly conserved in m ammals and across evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated b y our laboratory. This tool's pathogenic prediction is estimated to be correct 9 4% of the time (Jordan 2011). In summary, the clinical significance of the Glu18 83Lys variant is uncertain. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Jul 26, 2021	NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys) The c.5647G>A (p.Glu1883Lys) variant in MYH7 has been reported in the homozygous state in 1 individual from a consanguineous family with myosin storage myopathy, HCM and a family history consistent with recessive inheritance (Tajharghi 2007 PMID 17372140) and in 4 individuals with HCM from testing laboratories (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has been identified in 0.01% (1/18716) of African/African American chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but absent from all other populations (PM2). In vitro functional studies provide conflicting evidence on the impact of this on protein function, with some suggesting a potential impact (Viswanathan 2017 PMID: 28973424; Armel 2009 PMID: 19336582), while another suggests that it has a similar function as its wild time counterpart (Dahl-Halvarsson PMID 28125727). Therefore, this data is currently insufficient to establish functional impact and apply PS3. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1883 of the MYH7 protein (p.Glu1883Lys). This variant is present in population databases (rs121913652, gnomAD 0.01%). This missense change has been observed in individual(s) with myosin storage myopathy and hypertrophic cardiomyopathy (PMID: 17372140, 27532257). ClinVar contains an entry for this variant (Variation ID: 14121). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYH7 function (PMID: 28125727, 28973424). 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. -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 15, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2018

This variant is denoted Glu1883Lys (aka E1883K) at the protein level and c.5647 G>A at the cDNA level. Tajsharghi et al. (2007) reported the homozygous Glu1883Lys variant in a 44 year old man with myopathy and biventricular hypertrophic cardiomyopathy, among other features. This individual had two affected siblings who presented with myopathy and both died of cardiac failure prior to genetic testing. The parents were consanguinous and unaffected, although presumed heterozygous carriers of Glu1883Lys. The Glu1883Lys mutation is located in the distal end of the filament forming rod region of the MYH7 protein, which is essential for filament assembly. Other mutations in the same domain (Arg1845Trp, Glu1886Lys) have been reported in association with skeletal myopathy and hypertrophic cardiomyopathy, respectively (Tajsharghi et al 2003; Armel et al. 2009), supporting the functional importance of this region of the protein. Furthermore, Glu1883Lys was not observed in up to 400 chromosomes of Caucasian and African American ethnic backgrounds tested at GeneDx, indicating it is not a common benign polymorphism in these populations. The Glu1883Lys variant also has been observed in other unrelated individuals tested for HCM at GeneDx. In summary, with the clinical and molecular information available at this time, we can not conclude unequivocally that the Glu1883Lys variant is a disease-causing mutation or rare benign variant. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.96

MutPred

0.73

Gain of MoRF binding (P = 0.002);

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.1

Varity_R

0.49

gMVP

0.97

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