14-23429807-C-T

Variant names:

• chr14-23429807-C-T
• rs397516089
• NM_000257.4:c.1106G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS4 PM2 PM6 PP1

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.1106G>A (p.Arg369Gln) variant has been identified in >20 individuals with DCM, including 1 individual who also had LVNC (PS4; Lakdawala 2012 PMID:22464770; Pugh 2014 PMID:24503780; Klauke 2017 PMID:29253866; Walsh 2017 PMID:27532257; Horvat 2019 PMID:29892087; Quiat 2020 PMID:32458740; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; Mayo clinic pers. comm.; OMGL pers comm.) and at least 2 individuals with assumed de novo occurrences (PM6; Lakdawala 2012 PMID:22464770; Quiat 2020 PMID:32458740; Klauke 2017 PMID:29253866; LMM pers. comm.). This variant was also identified in >10 individuals with isolated LVNC, including 1 with an assumed de novo occurrence (Dellefave 2009 PMID:20031619; Hoedemaekers 2010 PMID:20530761; Tian 2015 PMID:24691700; Li 2018 PMID:30371277; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm). This variant segregated with DCM in at least 3 affected individuals from 3 families (PP1; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.), and with LVNC in at least 5 individuals from 4 families (Centenary Institute Sydney pers. comm.; LMM pers. comm.; OMGL pers. comm.) . This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1, PM6, PM2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA010192/MONDO:0005021/002

• 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:14
• Conservation: PhyloP100: 5.93
• Publications: 20 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: Likely_pathogenic. The variant received 9 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.
• 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.1106G>A	p.Arg369Gln	missense	Exon 12 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.1106G>A	p.Arg369Gln	missense	Exon 11 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.1106G>A	p.Arg369Gln	missense	Exon 12 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.1106G>A	p.Arg369Gln	missense	Exon 12 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.1106G>A	p.Arg369Gln	missense	Exon 12 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460990 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726804

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

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: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5080

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Dilated cardiomyopathy 1S (3)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Myosin storage myopathy (2)
2	-	-	not provided (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	MYH7-related disorder (1)
1	-	-	Primary dilated cardiomyopathy (1)
1	-	-	Primary dilated cardiomyopathy;C1960469:Left ventricular noncompaction (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.048	B
Vest4		0.82
MutPred		0.84		Gain of ubiquitination at K367 (P = 0.0443)
MVP		0.89
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.89
gMVP		0.65
Mutation Taster		=5/95	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: rs397516089; hg19: chr14-23899016;