rs397516241

chr14-23415252-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000257.4(MYH7):c.5302G>A(p.Glu1768Lys) variant causes a missense change. 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1768M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 5.30

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 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000257.4
• 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, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.5302G>A	p.Glu1768Lys	missense_variant	37/40	ENST00000355349.4
MYH7	NM_001407004.1	c.5302G>A	p.Glu1768Lys	missense_variant	36/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.5302G>A	p.Glu1768Lys	missense_variant	37/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Mar 22, 2021	The c.5302G>A (p.Glu1768Lys) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Murphy 2016 PMID:26914223; Berge 2014 PMID:24111713; Homburger 2016 PMID:27247418; Cecconi 2016 PMID:27600940; LMM SCV000059606.5). In vitro studies showed this variant had a slight effect on protein structure, but no effect on the ability to incorporate into muscle sarcomeres in an experimental system (Wolny 2013 PMID:24047955); however, this evidence is insufficient to apply PS3. Additionally this variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). 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_Moderate; PM2; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYH7 function (PMID: 24047955). 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: 43059). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 15358028, 24111713, 24510615, 27247418, 27600940). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1768 of the MYH7 protein (p.Glu1768Lys). -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2014	Variant classified as Uncertain Significance - Favor Pathogenic. The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM a nd in 1 affected relative with syncope. It was absent from large population stud ies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and acr oss evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 09, 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.Glu1768Lys, E1768K, (c.5302G>A) in the MYH7 gene. We had initially classified this variant as likely disease causing, however, given the weak case data and the lack of Asian controls, we reclassified it to variant of uncertain significance, probably disease causing in 2014. We now have Asian frequency data from ExAC showing it is rare in that population. Thus we are increasingly feel it is more likely that this variant is in fact disease causing, however it remains classified as a variant of uncertain significance, probably disease. An additional case would probably shift it to likely disease causing. The variant has been seen in at least three patients and possibly as many as five presumably unrelated patients with HCM, not including this patient. Van Driest et al., 2004 reported the variant in a cohort of 350 individuals with HCM, with no specific case data available for this variant, including ancestry data. Bos et al (2014) reported the variant in two patients with HCM in their Mayo cohort who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and with the clinical labs since some of these patients likely underwent clinical genetic testing. These two cases also likely overlap with two of the three reported by Kapplinger et al (2014) since that dataset includes Mayo cases and patients referred to Transgenomic for genetic testing. Unfortunately phenotypic data is not provided and so we cannot confirm if cases tested at Transgenomic had HCM. This variant has also been seen in another individual in our center with HCM, also of Asian ancestry. LMM's ClinVar assertion is "uncertain significance", with the following data: "The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM and in 1 affected relative with syncope. It was absent from large population studies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and across evolutionarily distant species and the change to lysine (Lys) 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 suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain." This variant is in the rod portion of MYH7 (exons 24-40) No segregation data is available. This variant changes a polar, acidic glutamic acid to a polar basic lysine. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts it to be disease causing. The glutamic acid at codon 1768 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with cardiomyopathy at nearby codons (Leu1769Met, Klassen et al 2008; Ala1766Thr, Girolamni et al 2006). The variant was reported online in 1 of 60,705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 24th, 2015). The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2015

The E1768K variant in the MYH7 gene has been reported previously in association with HCM and it was not observed in 400 control alleles from individuals of African American and Caucasian ethnic backgrounds (Van Driest et al., 2004). The E1768K variant 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. E1768K results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine residue at a position that is highly conserved throughout evolution. Furthermore, missense variants in nearby residues (A1763T, A1766T, L1769M) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Additionally, E1768K has been observed in multiple unrelated individuals tested for HCM Nevertheless, functional studies show that the E1768K variant had MHC incorporation into myofibrils similar to wild type cells (Wolny et al., 2013). Finally, another clinical laboratory classifies E1768K as a variant of uncertain significance in ClinVar (Landrum et al., 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.78		Gain of MoRF binding (P = 0.0041);
MVP		0.94
MPC		1.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.64
gMVP		0.96

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: rs397516241; hg19: chr14-23884461;