rs727504753

Positions:

• chr14-23429345-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.1141G>A (p.Ala381Thr) variant has been identified in 1 neonate with HCM and repolarization abnormalities (LMM pers. comm.); however this case data is insufficient to apply PS4. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA010273/MONDO:0005045/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense, splice_region
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 4.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1141G>A	p.Ala381Thr	missense_variant, splice_region_variant	13/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1141G>A	p.Ala381Thr	missense_variant, splice_region_variant	12/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1141G>A	p.Ala381Thr	missense_variant, splice_region_variant	13/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 29, 2013

The Ala381Thr variant in MYH7 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do no t provide strong support for or against an impact to the normal function of the protein. At this time, additional information is needed to fully assess the clin ical significance of the Ala381Thr variant. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Cardiomyopathy Variant Curation Expert Panel

Sep 22, 2021

The NM_000257.4(MYH7):c.1141G>A (p.Ala381Thr) variant has been identified in 1 neonate with HCM and repolarization abnormalities (LMM pers. comm.); however this case data is insufficient to apply PS4. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PM1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.036
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		0.0030	B
Vest4		0.49
MutPred		0.57		Gain of catalytic residue at Y386 (P = 0.0443);
MVP		0.94
MPC		1.7
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.67
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504753; hg19: chr14-23898554;