14-23418313-C-T

Position:

chr14-23418313-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP1_StrongPS4

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys) variant has been identified in at least 40 individuals with HCM, including 1 with features of RCM (PS4; Brito 2005 PMID:16335287; Van Driest 2004 PMID:15358028; Perrot 2005 PMID:15856146; Theis 2009 PMID:19808356; Brito 2012 PMID:22857948; Zou 2013 PMID:23283745; Lopes 2013 PMID:23396983; Núñez 2013 PMID:23782526; Captur 2014 PMID:24704860; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Mademont-Soler 2017 PMID:28771489; Lu 2018 PMID:30165862; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregates with HCM in at least 10 relatives from 5 families (PP1_Strong; LMM pers. comm.; OMGL pers. comm.; Stanford Inherited Heart Center pers. comm.). This variant was also reported to segregate with disease in a family with HCM, although details were not provided (Brito 2012 PMID:22857948). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant alters protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Armel 2010 PMID:19913502; Wolny 2013 PMID:24047955). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014400/MONDO:0005045/002

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9U:1

Conservation

PhyloP100: 7.63

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 Pathogenic. Variant got 11 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.

PP1

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 linkuse as main transcript	c.4066G>A	p.Glu1356Lys	missense_variant	30/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.4066G>A	p.Glu1356Lys	missense_variant	29/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.4066G>A	p.Glu1356Lys	missense_variant	30/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

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

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461348

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726986

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

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:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 25, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 18, 2012	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.Glu1356Lys (c. 4066G>A) in the MYH7 gene. We first reviewed this variant in June 2011, we reviewed it on 1/25/2012, adding additional control data. There was no new case data at that time. We last reviewed it on 4/17/13 adding additional control and case data. We are aware of a total of at least 4 presumably unrelated individuals who have this variant and have cardiomyopathy (not including this family). This variant has been reported in 4 unrelated individuals with HCM (Van Driest et al 2004, Millat et al 2010, Perrot et al 2005, Brito, 2011). Brito et al the variant segregated with disease, although specifics are not given. Theis et al (2009) also reported a case with this variant, however it may be the same case that was reported by Van Driest et al (2004). Moderate segregation data is available within our patient's family. This is a semi conservative amino acid change with a polar, negative glutamic acid replaced by a polar, positive lysine. Conservation analysis illustrates that glutamic acid is highly conserved across species at codon 1356 (Perrot et al 2005). There are no published disease associated variants within 10 codons upstream or downstream of this variant. Functional studies indicate that the presence of p.Glu1356Lys thermodynamically destabilizes the resulting myosin heavy chain protein and affecting its ability to form filaments and to function properly (Armel et al 2009). LMM informed me that a novel computational tool specific to sarcomere genes and based on PolyPhen predicts the variant to be pathogenic. This tool has a reported accuracy of 94% (Jordan 2011). In total, this variant was not observed in ~7,296 published controls, laboratory controls, and publicly available general population samples. Note that the family's ancestry is Asian, and few of these controls are matched to that ancestry. PGxHealth reports that they did not see this variant in 400 presumably healthy controls of mixed ethnic background. Perrot et al did not find the variant in 96 healthy volunteers of unspecified race. Brito did not find the variant in 100 additional samples of unspecified race. Van Driest et al did not identify the variant in 100 Caucasian and 100 African American controls. There is no variation at codon 1356 listed in dbSNP (as of 4/17/13). There are two entries for variant at codon 1356 listed in 1000 genomes, however one points to an HGMD entry and the other is rom COSMIC project (somatic mutations found in human cancers) (April 17th, 2013). There is also no variation at codon 1356 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 4/17/2013). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	In vivo studies suggested this variant may lead to reduced sarcomere incorporation of myosin, but adverse effects on muscle contraction were not observed (PMID: 24047955); In vitro functional analysis demonstrated decreased thermal stability and decreased ability to form filaments, though the filaments that did form were indistinguishable from wild-type and contraction was not significantly affected (PMID: 19913502); 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, 15856146, 15358028, 23782526, 32894683, 28687478, 25125180, 23396983, 25649125, 26688388, 19808356, 23074333, 22857948, 24704860, 27532257, 27247418, 29300372, 23283745, 20800588, 25351510, 28408708, 28771489, 30165862, 31737537, 31199839, 32344918, 16335287, 34352619, 34428338, 35050212, 33658040, 32686758, 28615295, 33407484, 30297972, 35653365, 28193612, 34542152, 36291626, 19913502, 24047955) -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 30, 2021	The NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys) variant has been identified in at least 40 individuals with HCM, including 1 with features of RCM (PS4; Brito 2005 PMID: 16335287; Van Driest 2004 PMID: 15358028; Perrot 2005 PMID: 15856146; Theis 2009 PMID: 19808356; Brito 2012 PMID: 22857948; Zou 2013 PMID: 23283745; Lopes 2013 PMID: 23396983; Núñez 2013 PMID: 23782526; Captur 2014 PMID: 24704860; Homburger 2016 PMID: 27247418; Walsh 2017 PMID: 27532257; Mademont-Soler 2017 PMID: 28771489; Lu 2018 PMID: 30165862; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregates with HCM in at least 10 relatives from 5 families (PP1_Strong; LMM pers. comm.; OMGL pers. comm.; Stanford Inherited Heart Center pers. comm.). This variant was also reported to segregate with disease in a family with HCM, although details were not provided (Brito 2012 PMID: 22857948). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant alters protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Armel 2010 PMID: 19913502; Wolny 2013 PMID: 24047955). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1356 of the MYH7 protein (p.Glu1356Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 15856146, 19913502, 20800588, 22857948). ClinVar contains an entry for this variant (Variation ID: 164294). 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: 24047955). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 22, 2019

This missense variant is located in the LMM domain of the MYH7 protein, C-terminal tail region that forms the thick filament backbone and interacts with other proteins. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have suggested that this variant may thermodynamically destabilize the protein (PMID: 19913502) and reduce incorporation of the mutant protein into the sarcomeres (PMID: 24047955). However, the variant did not significantly affected muscle contraction (PMID: 24047955). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 28771489, 23283745, 22857948, 20800588, 19808356, 15856146, 15358028) and reported to segregate with disease in a family although detailed data are not available (PMID: 22857948). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy;C0520806:Sudden unexplained death

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Dec 05, 2019

This MYH7 Glu1356Lys variant has previously been identified in >15 unrelated HCM cases (see references, ClinVar submissions), including 1 de novo occurence (Brito et al., 2005). The variant has also been reported to segregate in 2 affected families (Standford University, Pers Comm.). A biochemical and biophysical assay has shown that the variant destabilises the protein and impairs filament formation (Armel TZ & Leinwand LA, 2010), whereas expression in adult rat cardiomyocytes suggests that this variant alters the alpha-helical structure, resulting in improper sarcomeric incorporation (Wolny M, et al., 2013). We identified this variant in 1 individual diagnosed with HCM (Ingles et al., 2017). MYH7 Glu1356Lys is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict the variant to be deleterious. In summary, based on this information, we classify MYH7 Glu1356Lys as "pathogenic". -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The p.E1356K pathogenic mutation (also known as c.4066G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4066. The glutamic acid at codon 1356 is replaced by lysine, an amino acid with similar properties. This variant has been reported in several patients with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in several families (Van Driest SL et al. J Am Coll Cardiol. 2004;44:602-10; Perrot A et al. J Mol Med. 2005;83:468-77; Millat G et al. Clin Chim Acta. 2010;411:1983-91; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Homburger JR et al. Proc Natl Acad Sci U.S.A. 2016;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; external communication). In functional in vitro and in vivo analyses, this variant has been suggested to adversely affect thick filament assembly in the sarcomere; however, the clinical impact of these findings has not been determined (Armel TZ et al. Biochem Biophys Res Commun. 2010;391:352-6; Wolny M et al. J Biol Chem. 2013;288:31952-62). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant was co-segregated with Cardiomyopathy, hypertrophic,1 in multiple affected family members with additional meioses (PMID: 30297972, PP1_M). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 19808356, 23396983, 15856146, 27532257, 22857948, 24704860, 30297972, PS4_S). A different missense change at the same codon has been reported to be associated with MYH7 related disorder (PMID:NULL, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.848, 3CNET: 0.909, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 07, 2014

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.057

Polyphen

0.90

Vest4

0.95

MutPred

0.72

Gain of ubiquitination at E1356 (P = 0.0114);

MVP

0.97

MPC

1.6

ClinPred

1.0

GERP RS

4.8

Varity_R

0.53

gMVP

0.86

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