rs727504310

Positions:

• chr14-23424909-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM1 PP1_Strong PS4

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu) variant has been identified in >50 individuals with HCM (PS4; Atiga 2000 PMID:10725281; Kaski 2009 PMID:20031618; Aletras 2011 PMID:21576279; Leung 2013 PMID:23271734; Nunez 2013 PMID:23782526; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ross 2017 PMID:28615295; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute pers. comm.). This variant segregated with disease in 7 affected individuals with HCM in 5 families (PP1_Strong; Ross 2017 PMID:28615295; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide evidence for or against an impact to the protein. 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, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012578/MONDO:0005045/002

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.61

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 Pathogenic. Variant got 12 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2539A>G	p.Lys847Glu	missense_variant	22/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2539A>G	p.Lys847Glu	missense_variant	21/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2539A>G	p.Lys847Glu	missense_variant	22/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 30, 2021	The NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu) variant has been identified in >50 individuals with HCM (PS4; Atiga 2000 PMID:10725281; Kaski 2009 PMID:20031618; Aletras 2011 PMID:21576279; Leung 2013 PMID:23271734; Nunez 2013 PMID:23782526; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ross 2017 PMID:28615295; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute pers. comm.). This variant segregated with disease in 7 affected individuals with HCM in 5 families (PP1_Strong; Ross 2017 PMID:28615295; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide evidence for or against an impact to the protein. 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, PM1. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 847 of the MYH7 protein (p.Lys847Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 20031618, 22857948, 23782526, 27247418, 27532257, 28615295). ClinVar contains an entry for this variant (Variation ID: 177757). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2021	The p.Lys847Glu variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (Fananapazir 1999 PMID: 10328076, Atiga 2000 PMID: 10725281, Kaski 2009 PMID: 20031618, Leung 2013 PMID: 23271734, Nunez 2013 PMID: 23782526, Walsh 2017 PMID: 27532257, Kelly 2018 PMID: 29300372, LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID 27532257). Finally, this variant was classified as Likely Pathogenic on December 15, 2016 by the ClinGen-approved Inherited Cardiomyopathy Variant Curation expert panel (Variation ID 177757). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PS4, PM1, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 03, 2024	The c.2539A>G (p.Lys847Glu) variant in the MYH7 gene has been identified in numerous (>25) individuals affected with the consistent phenotype of hypertrophic cardiomyopathy (HCM) and segregated with disease in seven affected individuals from five families (PMID:10725281, 20031618, 21576279, 23782526, 27532257, 28615295, ClinGen review [ClinVar ID: 177757]). This variant lies in the established functional domain (amino acids 167-931) of the MYH7 protein without benign variations and missense variants in this region are statistically more likely to be disease-associated (PMID: 27532257, 27247418). This variant is found to be rare (2/1614202; 0.0001239%) in the general population database, gnomAD (v4.1.0) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database including the ClinGen cardiomyopathy variant curation expert panel (ClinVar ID:177757). Therefore, the c.2539A>G (p.Lys847Glu) variant in the MYH7 gene is classified as pathogenic. -

Hypertrophic cardiomyopathy 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established However, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid (exon 22). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 29300372). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as disease causing in multiple individuals (ClinVar, PMID: 29300372, 28408708). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Apr 22, 2015	The MYH7 Lys847Glu variant has been reported in multiple unrelated HCM patients (Atiga 2000 , Kaski 2009, Aletras 2011, Brito 2012, Leung 2013, Nunez 2013) and was absent in large population studies of >200 normal controls (Brito D et al., 2012; Nunez L et al., 2013; Kaski J et al., 2009). This variant has been identified in childhood HCM (Kaski, 2009) as well as adult-onset HCM (see references). This variant is also absent from both the 1000 genomes project (http://www.1000genomes.org/) and the from the large Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in 1 HCM patient who has no family history of disease or SCD. Lysine (Lys) at position 847 is highly conserved across distantly related species, and in silico tools including SIFT, MutationTaster, and PolyPhen2, predict that the amino acid change to be "damaging". Additionally, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts that this MYH7 Lys847Glu variant is causative of the disease. Based on the absence of this variant in the general population, predictions from a number of in silico models, and the presence of this variant in multiple unrelated HCM patients in independent studies, we classify this variant as "likely pathogenic". Further supporting evidence such as segregation data and/or functional analysis will be required to reclassify this variant as pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 14, 2022

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 07, 2019

Variant summary: MYH7 c.2539A>G (p.Lys847Glu) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252322 control chromosomes. c.2539A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example Atiga_2007, Brito_2012, Kaski_2009, Leung_2013, Marston_2013, Nunez_2013, Homburger_2016, Walsh_2017, Ross_2017). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Leung_2013, Marston_2013). Four clinical diagnostic laboratories and one expert panel (ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=4). The expert panel classification as likely pathogenic may represent an outdated submission (2016). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2021

The p.K847E pathogenic mutation (also known as c.2539A>G), located in coding exon 20 of the MYH7 gene, results from an A to G substitution at nucleotide position 2539. The lysine at codon 847 is replaced by glutamic acid, 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 alteration has been detected in multiple individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts that underwent HCM genetic testing (Atiga WL et al. Circulation. 2000 Mar;101(11):1237-42; Kaski JP et al. Circ Cardiovasc Genet. 2009 Oct;2(5):436-41; Núñez L et al. Circ J. 2013 Jun;77(9):2358-65; Lopes LR. Heart et al. 2015 Feb;101(4):294-301; Homburger JR et al. Proc Natl Acad Sci USA. 2016 06;113(24):6701-6; Walsh R et al. Genet Med. 2017 Feb;19(2):192-203; Kelly MA. Genet Med. 2018 03;20(3):351-359; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.75
Sift	Benign	0.13	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.36		Loss of ubiquitination at K847 (P = 0.0051);
MVP		0.94
MPC		2.5
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.40
gMVP		0.97

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: rs727504310; hg19: chr14-23894118;