rs397516208

chr14-23417580-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Strong

The NM_000257.4(MYH7):c.4276G>A(p.Glu1426Lys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. E1426E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 7.69

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]

MHRT (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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, 0.968
• PP5: Variant 14-23417580-C-T is Pathogenic according to our data. Variant chr14-23417580-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 43005.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2, Likely_pathogenic=1}. Variant chr14-23417580-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4276G>A	p.Glu1426Lys	missense_variant	31/40	ENST00000355349.4
MHRT	NR_126491.1	n.861C>T		non_coding_transcript_exon_variant	6/6
MYH7	NM_001407004.1	c.4276G>A	p.Glu1426Lys	missense_variant	30/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4276G>A	p.Glu1426Lys	missense_variant	31/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Primary familial dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 08, 2019

Variant summary: MYH7 c.4276G>A (p.Glu1426Lys) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant was absent in 251934 control chromosomes (gnomAD and publication ACMG PM2). c.4276G>A has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy (Kelly_2018, Vikhorev_2017, Shipman_2011, Villard_2005). In one of these studies the variant was found to co-segregate with disease in 3 affected family members (Villard_2005). Additionally, the variant was also reported in one HCM patient as part of a large well genotyped study that included 7,855 cardiomyopathy cases although the authors classified the variant as a VUS (Walsh_2017). These data indicate that the variant is very likely to be associated with disease (ACMG PS4-moderate). Experimental evidence evaluating an impact on protein function demonstrated the variant protein to have faster relaxation kinetics and reduced passive stiffness compared to controls while the degree of cardiomyocyte apoptosis and interstitial cell apoptosis measured for the related sample was considerably increased compared to controls (Vikhorev_2017). Although, ClinGens Inherited Cardiomyopathy Expert Panel released recommendations stating that typically performed MYH7 in vitro assays were generally deemed to have relatively low positive predictive value (Kelly_2018), this publication by Vikhorev et al represents an in-vivo human tissue model representative of the pathophysiology associated with MYH7 related cardiomyopathy. The same expert panel classified c.4276G>A as a variant of uncertain significance (ClinVar, Kelly_2018). Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and once as likely pathogenic. The expert panel stated that ACMG PM1 was applicable mainly to variants located in the head region domain of MYH7 (amino acids 181-937) and that ACMG PP2 was deemed not applicable for variants located outside the head domain to avoid double counting in scenarios where ACMG PM1 could be applied. However, we believe that the ACMG PP2 rule for MYH7 can still apply for variants located outside the head domain where the ACMG PM1 evidence has not been engaged. Based on the evidence outlined above and utilizing ClinGens expert panels adapted criteria PM2, PP3 and PS4_Moderate (i.e. variant identified in greater than or equal to 6 probands with consistent phenotypes) in conjunction with ACMG PP2 and ACMG PS3 the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2023

Identified in patients with DCM in published literature (Villard et al., 2005; Verdonschot et al., 2020; Pezzoli et al., 2021); Reported in a female with a non-dilated left ventricle, severe global impairment of systolic function and moderate mitral regurgitation on echocardiogram, who presented after chemotherapy and radiotherapy treatment for breast cancer; the family history was remarkable for DCM and sudden death (Shipman et al., 2011); 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: 25961035, 16416045, 22610119, 30065175, 23302633, 18555187, 22337857, 25332820, 24474197, 29093449, 29300372, 27532257, 27802374, 32133438, 35050212, 21482996, 15769782, 32880476, 35653365) -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1426 of the MYH7 protein (p.Glu1426Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 15769782, 21482996, 27532257, 32880476; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43005). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 29093449). 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

Apr 18, 2014

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

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Cardiomyopathy Variant Curation Expert Panel

Sep 22, 2021

The NM_000257.4 (MYH7): c.4276G>A (p.Glu1426Lys) variant has been identified in 5 individuals with DCM (PS4_Supporting; Villard 2005 PMID: 1576978; Shipman 2011 PMID: 21482996; Vikhorev 2017 PMID: 29093449; GeneDx pers. comm.; LMM pers. comm.), including as a de novo occurrence in 1 infant with an additional variant in a cardiomyopathy-associated gene (GeneDx pers. comm.) and in 1 individual with HCM (Walsh 2017 PMID: 27532257; OMGL pers. comm.). Because of the additional variant observed in the individual with the de novo occurrence, the PM6 criterion was not applied. This variant has also been reported in 1 individual with LVNC and reduced ejection fraction and in 1 individual with familial nondilated cardiomyopathy and their child with LVNC (Ambry pers. comm.; Invitae pers. comm). This variant segregated with disease in 2 affected relatives with DCM from 1 family (Villard 2005 PMID: 1576978); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2018

The p.E1426K variant (also known as c.4276G>A), located in coding exon 29 of the MYH7 gene, results from a G to A substitution at nucleotide position 4276. The glutamic acid at codon 1426 is replaced by lysine, an amino acid with similar properties, and is located in the tail domain. This alteration was detected in two individuals with dilated cardiomyopathy (DCM) and presumed present in an affected obligate carrier in one family (Villard E et al. Eur. Heart J., 2005 Apr;26:794-803). In another family, this alteration was detected in a patient with cardiomegaly, non-dilated LV, impaired systolic function, and syncope, however, this individual had undergone chemotherapy and radiotherapy. The alteration was also detected on post mortem testing in her daughter with reported history of DCM and sudden death, although clinical details were limited (Shipman KE et al. J. Clin. Oncol., 2011 Jun;29:e537-8). This alteration was also detected in a cohort of individuals undergoing genetic testing for hypertrophic cardiomyopathy (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). One in vitro functional study of cardiac myofibrils from a patient sample indicated this alteration to result in decreased passive stiffness and possible altered calcium sensitivity (Vikhorev PG et al. Sci Rep, 2017 Nov;7:14829). Furthermore, ClinGen's Inherited Cardiomyopathy Expert Panel classifies this alteration as a variant of unknown significance (Kelly MA et al. Genet. Med., 2018 03;20:351-359). 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	Pathogenic	0.99
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.77		Gain of MoRF binding (P = 0.0045);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.53
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: rs397516208; hg19: chr14-23886789; COSMIC: COSV62519182; COSMIC: COSV62519182;