rs727504311

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000257.4(MYH7):c.2543A>G(p.Glu848Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.61

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 Pathogenic. Variant got 15 ACMG points.

PM1

In a helix (size 120) in uniprot entity MYH7_HUMAN there are 91 pathogenic changes around while only 3 benign (97%) in NM_000257.4

PM2

Very rare variant in population databases, with high coverage;

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 hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

PP5

Variant 14-23424905-T-C is Pathogenic according to our data. Variant chr14-23424905-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424905-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.2543A>G	p.Glu848Gly	missense_variant	Exon 22 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.2543A>G	p.Glu848Gly	missense_variant	Exon 21 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.2543A>G	p.Glu848Gly	missense_variant	Exon 22 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:2

May 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu848Gly variant in MYH7 has been identified in at least 6 individuals wi th HCM and segregated with disease in one affected family member (Alfares 2015, GeneDx pers. comm., LMM data). This variant was absent from large population stu dies. In vitro functional studies provide some evidence that the p.Glu848Gly va riant may impact protein function (Pioner 2016); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Glu848Gly variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. Of note, this variant lies in the head region of the protein. Missense vari ants in this region have been reported and statistically indicated to be more li kely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu848Gly variant i s likely pathogenic. ACMG/AMP criteria applied: PM1, PM2, P23_Moderate, PS4_Mode rate, PP3. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 848 of the MYH7 protein (p.Glu848Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27161364, 27532257, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 177758). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 30623132). 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. -

not provided

Pathogenic:1

Jun 22, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 177758; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Functional studies using stem cells suggest that this variant changes contractile properties leading to cardiomyopathy (Pioner et al., 2016; Yang et al., 2018); 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, 27161364, 25611685, 28606303, 30623132) -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Feb 05, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.2543A>G (p.Glu848Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246248 control chromosomes (gnomAD). It is reported in the Atlas of Cardiac Genetic Variation database to occur in the region enriched for HCM mutations (residues 181-937) and is scored with a high etiological fraction (0.97) (in general, missense variants in MYH7 have an overall etiological fraction of 0.92). c.2543A>G has been reported in the literature in an individual affected with Hypertrophic Cardiomyopathy (Alfares_2015) and was shown to co-segregate with disease in a pedigree affected with familial cardiomyopathy (FCM) with adult-onset systolic dysfunction (Yang_2018). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function report this variant to result in contractile dysfunction of myofibrils (Pioner_2016) by disruption of the myosin S2 and cMyBP-C C1C2 protein-protein interaction (Yang_2018; Pioner_2016) on measures of maximal isometric tension generation (Pioner_2016) and lack of growth in yeast-two hybrid assay (Yang_2018). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Oct 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E848G variant (also known as c.2543A>G), located in coding exon 20 of the MYH7 gene, results from an A to G substitution at nucleotide position 2543. The glutamic acid at codon 848 is replaced by glycine, an amino acid with 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 variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy (HCM), and segregated with disease in one family in which affected individuals first demonstrated systolic dysfunction and arrhythmias prior to myocardial hypertrophy (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Pioner JM et al. Stem Cell Reports, 2016 Jun;6:885-896; Loiben AM et al. Int J Mol Sci, 2023 Mar;24; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.5

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.94

MutPred

0.40

Gain of MoRF binding (P = 0.0245);

MVP

0.96

MPC

2.3

ClinPred

1.0

GERP RS

4.7

Varity_R

0.59

gMVP

0.99

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