rs369437262

Variant names:

• chr14-23415228-T-C
• rs369437262
• NM_000257.4:c.5326A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID:30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). 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 uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA015944/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:21
• Conservation: PhyloP100: 7.75
• 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]

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

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.5326A>G	p.Ser1776Gly	missense	Exon 37 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5326A>G	p.Ser1776Gly	missense	Exon 36 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.-222T>C		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.5326A>G	p.Ser1776Gly	missense	Exon 37 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.5371A>G	p.Ser1791Gly	missense	Exon 37 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.5371A>G	p.Ser1791Gly	missense	Exon 37 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251494 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461894 Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16 AN XY: 727248

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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: 0.000646 AC: 39 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

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

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	3	-	Cardiomyopathy (3)
-	3	-	Hypertrophic cardiomyopathy (3)
-	3	-	not specified (3)
-	2	-	Hypertrophic cardiomyopathy 1 (2)
-	1	-	Cardiovascular phenotype (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 disorder (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Uncertain	0.28
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.044	D
Polyphen		0.80	P
Vest4		0.93
MutPred		0.41		Loss of phosphorylation at S1776 (P = 0.0274)
MVP		0.88
MPC		1.5
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.90
Mutation Taster		=8/92	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: rs369437262; hg19: chr14-23884437;