14-23423984-C-T

Variant names:

• chr14-23423984-C-T
• rs121913629
• NM_000257.4:c.2845G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PM2 PM6 PP3

This summary comes from the ClinGen Evidence Repository: The c.2845G>A (p.Glu949Lys) variant in MYH7 has been reported in 12 individuals with HCM (PS4_Moderate; Watkins 1992 PMID:1552912; Walsh 2017 PMID:27532257; Zigova 2018 PMID:28815794; CHEO pers comm.). This variant segregated with disease in 1 affected relative with HCM (Watkins 1992 PMID:1552912); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has been reported as a de novo occurence in 1 child with RCM (PM6; Kapoor 2017 http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM6; PM2; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA013144/MONDO:0005045/002

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 7.74
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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: Likely_pathogenic. The variant received 7 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.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2845G>A	p.Glu949Lys	missense	Exon 23 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.2845G>A	p.Glu949Lys	missense	Exon 22 of 39	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.2845G>A	p.Glu949Lys	missense	Exon 23 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.2845G>A	p.Glu949Lys	missense	Exon 23 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.2845G>A	p.Glu949Lys	missense	Exon 22 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 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: 8.99e-7 AC: 1 AN: 1112012

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Mar 22, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2845G>A (p.Glu949Lys) variant in MYH7 has been reported in 12 individuals with HCM (PS4_Moderate; Watkins 1992 PMID:1552912; Walsh 2017 PMID:27532257; Zigova 2018 PMID:28815794; CHEO pers comm.). This variant segregated with disease in 1 affected relative with HCM (Watkins 1992 PMID:1552912); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has been reported as a de novo occurence in 1 child with RCM (PM6; Kapoor 2017 http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM6; PM2; PP3

Jul 28, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu949Lys variant in MYH7 has been reported in >11 individuals with hypertrophic cardiomyopathy (HCM) and as a de novo occurrence in 1 individual with restrictive cardiomyopathy (RCM) and segregated with disease in 1 affected individual from 1 family (Watkins 1992 PMID: 1552912, Kapoor 2017, Zigova 2017 PMID: 28815794, Walsh 2017 PMID: 27532257/LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as Likely Pathogenic on March 22, 2021 by the ClinGen-approved Cardiomyopathy Variant Curation expert panel (Variation ID 14093). 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 HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM6, PM2_Supporting, PP3.

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 949 of the MYH7 protein (p.Glu949Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or restrictive cardiomyopathy (PMID: 1552912, 27532257, 28815794; http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14093). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Cardiomyopathy Pathogenic:1 Uncertain:1

Feb 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 949 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 1552912, 25611685, 27532257, 28815794, 33495597), and in one individual affected with restrictive cardiomyopathy (doi:10.1186/1755-8166-7-S1-P34 Kapoor 2014). In one family, this variant has been reported in two affected individuals (PMID: 1552912). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Apr 14, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary dilated cardiomyopathy Pathogenic:1

Dec 11, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2845G>A (p.Glu949Lys) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least twelve individuals affected with Hypertrophic Cardiomyopathy (HCM) (ClinGen Expert Panel review [ClinVar ID: 14093], PMID:1552912, 27532257, 28815794, 1552912). This variant has been reported as de novo status in a proband with restrictive cardiomyopathy (ClinVar ID: 14093, PMID: NA). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.909). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar ID: 14093). Therefore, the c.2845G>A (p.Glu949Lys) variant in the MYH7 gene is classified as likely pathogenic.

Hypertrophic cardiomyopathy 1 Pathogenic:1

Apr 23, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.98
MutPred		0.74		Gain of MoRF binding (P = 0.013)
MVP		0.95
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.99
Mutation Taster		=0/100	disease causing

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: rs121913629; hg19: chr14-23893193;