rs727503253

Variant names:

• chr14-23424119-G-A
• rs727503253
• NM_000257.4:c.2710C>T
• MYH7 p.Arg904Cys

Your query was ambiguous. Multiple possible variants found:

• chr14-23424119-G-A
• chr14-23424119-G-C
• chr14-23424119-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS4_Moderate PM2 PM6 PM5 PP3 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000257.4:c.2710C>T (p.Arg904Cys) variant in MYH7 has been identified in 4 individuals with DCM in the literature (1 of whom also had LVNC; van Spaendonck-Zwarts 2013 PMID:23349452; van der Zwaag 2011 PMID:20573160; Walsh 2017 PMID:27532257; Miller 2017 PMID29212898) and 3 individuals with LVNC (2 of which were pediatric; Yang 2014 PMID:25326635; Wang 2017 PMID:28855170; van Waning 2018 PMID:29447731). This variant was identified in 8 individuals with DCM and 1 proband with LVNC by clinical laboratories (GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm.). Only probands with DCM are counted towards PS4 (n=12; PS4_Moderate). This variant segregated with DCM in 15 affected individuals from 4 families (PP1_Strong; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.) and was assumed de novo in 1 of the above cases (PM6; GeneDx pers. comm.). This variant has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but was absent from all other populations. A different pathogenic missense variant has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5; c.2711G>A p.Arg904His - Variation ID 42926). 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Strong, PM6, PM2, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012904/MONDO:0005021/002

• 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:12
• Conservation: PhyloP100: 0.265
• Publications: 11 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hypertrophic cardiomyopathy

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

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

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 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.
• PM5: 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2710C>T	p.Arg904Cys	missense	Exon 23 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.2710C>T	p.Arg904Cys	missense	Exon 22 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.2710C>T	p.Arg904Cys	missense	Exon 23 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.2710C>T	p.Arg904Cys	missense	Exon 23 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.2710C>T	p.Arg904Cys	missense	Exon 23 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251442 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 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: 53404

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Dilated cardiomyopathy 1S (4)
3	-	-	Primary dilated cardiomyopathy (3)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Hypertrophic cardiomyopathy 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		0.27
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.71
gMVP		0.99
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs727503253;

hg19: chr14-23893328;

COSMIC: COSV62516033;