rs397516248

Positions:

• chr14-23415153-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM6 PM2 PP3 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5401G>A (p.Glu1801Lys) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy, one of whom had additional myopathy features (PS4_Supporting; PMID:19477645; Partners LMM ClinVar SCV000059616.5). Additionally, in two of the probands with dilated cardiomyopathy, the variant occurred de novo (PM6; Partners LMM ClinVar SCV000059616.5). This variant was absent from large population studies (PM2; http://exac.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 likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM6; PP3; PS4_ Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA016087/MONDO:0005021/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 6.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5401G>A	p.Glu1801Lys	missense_variant	37/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5401G>A	p.Glu1801Lys	missense_variant	36/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5401G>A	p.Glu1801Lys	missense_variant	37/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Neurogenetics Laboratory, Royal Perth Hospital	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 13, 2017	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2017	The E1801K likely pathogenic variant in the MYH7 gene has been reported in a Moldavian family with early onset distal myopathy and later onset, severe DCM (Udd et al., 2009). Lamont et al. (2014) also found E1801K in two members of an Israeli family with distal muscle weakness, and the proband was diagnosed with HCM at age 23. Ruggiero et al. (2015) identified the E1801K variant in three members of an Italian family with cardiomyopathy and distal myopathy. Additionally, E1801K has been observed in two infants tested at GeneDx for DCM. In each case, parental testing did not identify the E1801K variant, suggesting that these events occurred de novo. Similarly, the Laboratory for Molecular Medicine reports that E1801K has been observed in three infants with DCM tested at their laboratory, and was de novo in two of these cases (ClinVar SCV000059616.4; Landrum et al.,2016). E1801K results in a non-conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts E1801K is probably damaging to the protein structure/function. Furthermore, E1801K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although a variant at this same residue (E1801G) has been reported in association with cardiomyopathy (Stenson et al., 2014), the clinical significance of this variant has not been definitively determined. Therefore, this variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 23, 2022	- -

Primary dilated cardiomyopathy;C0027868:Neuromuscular disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 25, 2014

The p.Glu1801Lys variant in MYH7 has been reported in 1 individual with early on set distal myopathy and late onset DCM (Udd 2009) as well as 1 individual with e arly onset distal myopathy and HCM (Lamont 2014). The p.Glu1801Lys variant has a lso been identified by our laboratory in three infants with DCM and occurred de novo in two of them (LMM unpublished data). Additionally, this variant was abse nt from large population studies. Glutamic acid (Glu) is highly conserved in mam mals and across evolutionarily distant species and the change to lysine (Lys) wa s predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clin ical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic for Laing distal myopathy with cardiomyopathy in an au tosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) base d upon absence from controls and multiple de novo occurrences. -

Myosin storage myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jun 10, 2022

- -

Left ventricular noncompaction cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 20, 2015

- -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Cardiomyopathy Variant Curation Expert Panel

Dec 15, 2016

The c.5401G>A (p.Glu1801Lys) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy, one of whom had additional myopathy features (PS4_Supporting; PMID:19477645; Partners LMM ClinVar SCV000059616.5). Additionally, in two of the probands with dilated cardiomyopathy, the variant occurred de novo (PM6; Partners LMM ClinVar SCV000059616.5). This variant was absent from large population studies (PM2; http://exac.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 likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM6; PP3; PS4_ Supporting -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 43069). This missense change has been observed in individuals with autosomal dominant MYH7-related conditions (PMID: 19477645, 24503780, 24664454, 27532257, 28855170). It has also been observed to segregate with disease in related individuals. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1801 of the MYH7 protein (p.Glu1801Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.63		Gain of MoRF binding (P = 0.0056);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.70
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

Other links and lift over

dbSNP: rs397516248; hg19: chr14-23884362;