rs45520836

Positions:

chr14-23414074-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS4_ModeratePM2PP3

This summary comes from the ClinGen Evidence Repository: The c.5588G>A (p.Arg1863Gln) variant in MYH7 has been identified in 1 individual with familial DCM (Hershberger 2008 PMID:19412328) and 7 individuals with DCM from clinical testing laboratories (PS4_Moderate; PMID:19412328; Partners LMM ClinVar SCV000059623.5; Invitae ClinVar SCV000818269.1, pers. comm.; Ambry pers. comm.; CHEO ClinVar SCV000901909.1, pers. comm.; GeneDx ClinVar SCV000208646.4, pers. comm.). This variant was also identified in 0.00027% (FAF 95% CI; 2/129158) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016295/MONDO:0005021/002

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:8

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS4

PM2

PP3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5588G>A	p.Arg1863Gln	missense_variant	38/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5588G>A	p.Arg1863Gln	missense_variant	37/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5588G>A	p.Arg1863Gln	missense_variant	38/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251140

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000479

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000390

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 17, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces arginine with glutamine at codon 1863 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19412328, 29300372, 30847666). This variant has been identified in 3/282516 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2023	This missense variant replaces arginine with glutamine at codon 1863 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19412328, 29300372, 30847666). This variant has been identified in 3/282516 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. -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1863 of the MYH7 protein (p.Arg1863Gln). This variant is present in population databases (rs45520836, gnomAD 0.003%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19412328; Invitae). ClinVar contains an entry for this variant (Variation ID: 43076). 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. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 24, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1863Gl n variant in MYH7 has been reported in 1 individual with DCM (Hershberger 2008). This variant has also been identified by our laboratory in 1 male infant with D CM and Barth Syndrome who also carried a likely pathogenic variant in the TAZ ge ne. Both this variant and the likely pathogenic TAZ variant were also identified in 1 affected relative from the same family. This variant has been identified 1 /66706 European chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs45520836), but this likely represents the sample reported by Hershberger 2008 as this study was part of the NHLBI sequencing proj ect and is now included in ExAC. Arginine (Arg) at position 1863 is highly conse rved in mammals and across evolutionarily distant species and the change to glut amine (Gln) 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). In summary, while there is some suspic ion for a pathogenic role, the clinical significance of the p.Arg1863Gln variant is uncertain. -

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

Sep 15, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2023

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: 22337857, 23403236, 23299917, 27576561, 29300372, 32439065, 19412328) -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Cardiomyopathy Variant Curation Expert Panel

Mar 22, 2021

The c.5588G>A (p.Arg1863Gln) variant in MYH7 has been identified in 1 individual with familial DCM (Hershberger 2008 PMID:19412328) and 7 individuals with DCM from clinical testing laboratories (PS4_Moderate; PMID:19412328; Partners LMM ClinVar SCV000059623.5; Invitae ClinVar SCV000818269.1, pers. comm.; Ambry pers. comm.; CHEO ClinVar SCV000901909.1, pers. comm.; GeneDx ClinVar SCV000208646.4, pers. comm.). This variant was also identified in 0.00027% (FAF 95% CI; 2/129158) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2; PP3 -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The p.R1863Q variant (also known as c.5588G>A), located in coding exon 36 of the MYH7 gene, results from a G to A substitution at nucleotide position 5588. The arginine at codon 1863 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in an individual reported to have familial dilated cardiomyopathy, and has also been seen in an exome cohort, but cardiovascular history was not provided (Hershberger RE et al. Clin Transl Sci. 2008;1(1):21-6; Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28). This variant was also detected in one individual in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Pathogenic

0.84

CardioboostCm

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Benign

0.41

Polyphen

1.0

Vest4

0.89

MVP

0.97

MPC

1.7

ClinPred

1.0

GERP RS

5.1

Varity_R

0.72

gMVP

0.85

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