chr14-23417598-G-A

Variant names:

• chr14-23417598-G-A
• rs145213771
• NM_000257.4:c.4258C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4 PM2 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp) variant has been reported in >15 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease (PS4_Strong; Van Driest 2004 PMID:15358028; Millat 2010 PMID:20624503; Millat 2010 PMID:20800588; Teirlinck 2012 PMID:23140321; Zou 2013 PMID:23283745; Berge 2014 PMID:24111713; Ntusi 2016 PMID:27841901; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID:30297972; Gene Dx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.0003% (FAF 95% CI; 2/113756) of European chromosomes by gnomAD v2.1.1 (PM2; https://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 (PMID:29300372): PS4, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014718/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MYH7 ENST00000355349.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:19 U:1
• Conservation: PhyloP100: 1.77
• Publications: 14 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]

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355349.4. 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.4258C>T	p.Arg1420Trp	missense	Exon 31 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.4258C>T	p.Arg1420Trp	missense	Exon 30 of 39	NP_001393933.1
	MHRT	NR_126491.1		n.*3G>A		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4258C>T	p.Arg1420Trp	missense	Exon 31 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.4258C>T	p.Arg1420Trp	missense	Exon 31 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.4258C>T	p.Arg1420Trp	missense	Exon 30 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251476 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460406 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 726524

African (AFR) AF: 0.00 AC: 0 AN: 33434

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

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4528

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hypertrophic cardiomyopathy (4)
3	-	-	Cardiomyopathy (3)
2	-	-	Hypertrophic cardiomyopathy 1 (2)
2	-	-	Myosin storage myopathy (2)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
1	-	-	Dilated cardiomyopathy 1S (1)
1	-	-	Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
1	-	-	MYH7-related skeletal myopathy (1)
1	-	-	Myopathy, myosin storage, autosomal recessive (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		1.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.55
gMVP		0.95
Mutation Taster		=0/100	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: rs145213771; hg19: chr14-23886807;