rs727505033

Variant names:

• chr14-23415707-CTCCACCACGGCA-TTCTTCCACGGCC
• rs727505033
• NM_000257.4:c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000257.4(MYH7):​c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA​(p.Val1692Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R1689R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 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]

ENSG00000258444 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a helix (size 50) in uniprot entity MYH7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000257.4
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant		ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant			NP_001393933.1
MHRT	NR_126491.1	n.139_151delCTCCACCACGGCAinsTTCTTCCACGGCC		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant		1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant				ENSP00000519070.1
MYH7	ENST00000713769.1	c.5067_5079delTGCCGTGGTGGAGinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant				ENSP00000519071.1
ENSG00000258444	ENST00000557368.1	n.*21_*33delCTCCACCACGGCAinsTTCTTCCACGGCC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Val1692Glu variant in MYH7 has not been previously reported in individuals w ith cardiomyopathy and data from large population studies is insufficient to ass ess its frequency. This variant is a deletion and insertion of 13 bases that doe s not alter the proteins reading frame, resulting in the substitution of glutami c acid (Glu) for valine (Val) at position 1692. While valine is not well conserv ed in evolution, the change to glutamic acid was predicted to be pathogenic usin g a computational tool clinically validated by our laboratory. This tool's patho genic prediction is estimated to be correct 94% of the time (Jordan 2011). In su mmary, additional studies are needed to fully assess the clinical significance o f the Val1692Glu variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727505033; hg19: chr14-23884916;