rs397516224

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP5_Strong

The NM_000257.4(MYH7):c.457del(p.His153ThrfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:2

Conservation

PhyloP100: 9.75

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-23432683-TG-T is Pathogenic according to our data. Variant chr14-23432683-TG-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 43028.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.457del	p.His153ThrfsTer14	frameshift_variant	5/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.457del	p.His153ThrfsTer14	frameshift_variant	4/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.457del	p.His153ThrfsTer14	frameshift_variant	5/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251486

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 06, 2016

The p.His153ThrfsX14 variant in MYH7 has been identified in one individual with cardiomyopathy (in trans with another MYH7 variant) but has not been observed in large population studies. This variant is predicted to cause a frameshift, whic h alters the protein?s amino acid sequence beginning at position 153 and leads t o a premature termination codon 14 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Although heterozygous los s-of-function (LOF) variants in MYH7, such as this variant, are not believed to be pathogenic for the dominant condition more classically associated to MYH7, wh en a LOF variant is found in trans with another variant affecting function, a mo re severe and early-onset cardiomyopathy presentation can occur (LMM unpublished data). It should be noted that loss of function variants in the MYH7 gene are very rare and therefore an understanding of their potential impact is not well s tudied. In summary, this variant leads to a predicted loss-of-function of the pr otein and, although additional studies are required to fully establish its clini cal significance, it is likely pathogenic for a recessive presentation. -

Cardiomyopathy

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Cardiomyopathy Variant Curation Expert Panel

Aug 25, 2021

The c.457del (p.His153Thrfs*14) variant in MYH7 has been identified in a 6 month old with DCM that also had a second variant in MYH7 (LMM pers comm) as well as 2 cases in the literature without clinical information (Ceyhan-Birsoy 2019 PMID: 30609409; Zimmerman 2010 PMID: 20474083), which is insufficient to apply PS4_Supporting. This variant has been identified in 0.000879% (1/113760) of European (Non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift leading to a truncated or absent protein and the contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood. In summary, due to a lack of 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): PM2. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change creates a premature translational stop signal (p.His153Thrfs*14) in the MYH7 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 43028). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 20474083). This variant is present in population databases (rs397516224, gnomAD 0.0009%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over