rs727504310

Variant names:

• chr14-23424909-T-C
• rs727504310
• NM_000257.4:c.2539A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4 PM2 PM1 PP1_Strong

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:10
• Conservation: PhyloP100: 7.61
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2539A>G	p.Lys847Glu	missense	Exon 22 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.2539A>G	p.Lys847Glu	missense	Exon 21 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.2539A>G	p.Lys847Glu	missense	Exon 22 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.2539A>G	p.Lys847Glu	missense	Exon 22 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.2539A>G	p.Lys847Glu	missense	Exon 22 of 40	ENSP00000636014.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000570 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hypertrophic cardiomyopathy (4)
2	-	-	Cardiomyopathy (2)
2	-	-	Hypertrophic cardiomyopathy 1 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.6
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504310; hg19: chr14-23894118;