rs727503240

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate

The NM_000257.4(MYH7):c.5690G>A(p.Arg1897His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,110 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. R1897C) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000257.4

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5690G>A	p.Arg1897His	missense_variant	39/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5690G>A	p.Arg1897His	missense_variant	38/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5690G>A	p.Arg1897His	missense_variant	39/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

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:

0.00000398

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727248

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

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:

0.0000564

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	Identified with a second variant in a patient with Ebstein anomaly and left ventricular noncompaction in the literature (Mazzarotto et al., 2021); Identified in multiple patients with cardiomyopathy in the literature (Lopes et al., 2015; Hou et al., 2020); 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: 27532257, 35284542, 31983221, 31980526, 25351510, 33500567) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2022	This missense variant replaces arginine with histidine at codon 1897 of the MYH7 protein. Computational prediction suggests that this variant may have 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257), four individuals affected with left ventricular non-compaction (PMID: 33500567, ClinVar SCV001430834.1), and five individuals affected with dilated cardiomyopathy (PMID: 30847666, 31983221, 35284542, ClinVar SCV001430834.1). This variant has been identified in 1/251464 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	All of Us Research Program, National Institutes of Health	Jun 28, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 05, 2020

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

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jan 06, 2020

MYH7 Arg1897His has been reported multiple times in patients with varying and mixed phenotypes. It has been reported in at least 2 probands with hypertrophic cardiomyopathy (Walsh R, et al., 2017; Da Rocha Lopes LM, 2015) as well as 1 proband with childhood-onset dilated cardiomyopathy (Genedx, Pers. Comm.). A child with LVNC has been reported to carry this variant and an MYH7 splice variant (Praxis fuer Humangenetik Tuebingen, Pers. Comm.). The Laboratory of Molecular Medicine has identified this variant in a newborn with Epstein's anomoly, atrial septal defect, arrhythmia and LVNC, however they also had an MYH7 nonsense variant (Pers. Comm.). Invitae have identified this variant in a patient with DCM and non-compaction (Pers. Comm.). Finally, we have identified this variant in a proband with LVNC and possible DCM. The proband's child was diagnosed with LVNC and the variant was found to segregate to the child. MYH7 Arg1897His is present at a low frequency in the Genome Aggregation Database (AF= 0.000004; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen2, CADD predict this variant to be deleterious. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is rare in the general population (PM2), has been identified in multiple similar cases (PS4_Moderate) and in silico tools predict it to deleterious (PP3), therefore we classify MYH7 Arg1897His as a variant of 'uncertain significance'. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1897 of the MYH7 protein (p.Arg1897His). This variant is present in population databases (rs727503240, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy, left ventricular noncompaction (PMID: 25351510, 27532257, 31983221, 33500567; Invitae). ClinVar contains an entry for this variant (Variation ID: 164264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2022

The p.R1897H variant (also known as c.5690G>A), located in coding exon 37 of the MYH7 gene, results from a G to A substitution at nucleotide position 5690. The arginine at codon 1897 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in a variety of cardiomyopathy cohorts, including individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC); however, some individuals had co-occurring variants, and clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 02;19:192-203; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Mazzarotto F et al. Circulation, 2020 02;141:387-398; Hou YC et al. Proc Natl Acad Sci U S A, 2020 02;117:3053-3062; Harper AR et al. Nat Genet, 2021 02;53:135-142; Mazzarotto F et al. Genet Med, 2021 05;23:856-864). This amino acid position is highly 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

Uncertain

0.48

CardioboostCm

Uncertain

0.88

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.23

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.61

Loss of MoRF binding (P = 0.0555);

MVP

0.99

MPC

1.2

ClinPred

1.0

GERP RS

5.6

Varity_R

0.56

gMVP

0.92

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