rs200939753

Variant names:

• chr14-23415225-C-T
• rs200939753
• NM_000257.4:c.5329G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr) variant has been identified in at least 14 individuals with HCM, 2 of whom had an additional variant in another gene that may contribute to their disease, 1 individual with RCM with another pathogenic MYH7 variant, and 5 individuals with DCM including 2 that also had disease-causing variants (Richard 2003 PMID:12707239; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID:30297972; Ambry pers. comm.; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm). This variant has also been identified in 1 individual with LVNC requiring transplant who also had 2 pathogenic MYBPC3 variants, 1 individual with Brugada syndrome, and 2 individuals with myopathy - 1 with myofibrillar myopathy and 1 with distal and axial myopathy (Hertz 2014 PMID:25467552; Evilä 2016 PMID:26627873; Chanson 2016 PMID:26969127; Liu 2020 PMID:31918855). This variant has been observed to segregate with DCM in 1 relative of a proband with DCM as well as not segregate with HCM in an affected sibling of a proband with HCM (OMGL per. comm.). Because of the variability in phenotypes observed in individuals with this variant and because PS4 is only applicable when the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Additionally, the segregation data is currently insufficient to establish segregation or non-segregation with disease and therefore neither PP1 nor BS4 were applied. This variant has been identified in 0.008% (FAF 95% CI; 17/129,190) of European chromosomes in gnomAD v.2.1.1 (http://gnomad.broadinstitute.org) and is above the threshold of 0.004%, therefore PM2 cannot be applied. Computational prediction tools and conservation do not provide evidence for or against an impact to the protein. In summary, due to conflicting evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None. LINK:https://erepo.genome.network/evrepo/ui/classification/CA015952/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:13
• Conservation: PhyloP100: 3.85
• Publications: 9 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]

ENSG00000258444 (HGNC:):

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: Uncertain_significance. The variant received 0 ACMG points.

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.5329G>A	p.Ala1777Thr	missense	Exon 37 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5329G>A	p.Ala1777Thr	missense	Exon 36 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.-225C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.5329G>A	p.Ala1777Thr	missense	Exon 37 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.5374G>A	p.Ala1792Thr	missense	Exon 37 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.5374G>A	p.Ala1792Thr	missense	Exon 37 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251488 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.000102 AC XY: 74 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: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 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: 0.000136 AC: 151 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68048

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

Alfa AF: 0.0000356 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	Cardiomyopathy (3)
-	3	-	Hypertrophic cardiomyopathy 1 (3)
-	2	-	Hypertrophic cardiomyopathy (2)
-	2	-	not provided (2)
2	-	-	Primary familial hypertrophic cardiomyopathy (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	-	-	Idiopathic camptocormia (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostCm	Benign	0.064
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.028	D
Sift4G	Benign	0.19	T
Polyphen		0.98	D
Vest4		0.81
MutPred		0.42		Gain of phosphorylation at A1777 (P = 0.0699)
MVP		0.94
MPC		1.3
ClinPred		0.39	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.86
Mutation Taster		=16/84	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: rs200939753; hg19: chr14-23884434; COSMIC: COSV106494020; COSMIC: COSV106494020;