rs727505033

Positions:

• chr14-23415707-CTCCACCACGGCA-TTCTTCCACGGCC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The ENST00000355349.4(MYH7):​c.5067_5079delinsGGCCGTGGAAGAA​(p.Val1692Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 ENST00000355349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 50) in uniprot entity MYH7_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in ENST00000355349.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5067_5079delinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant	35/40	ENST00000355349.4	NP_000248.2
MHRT	NR_126491.1	n.139_151delinsTTCTTCCACGGCC		non_coding_transcript_exon_variant	2/6
MYH7	NM_001407004.1	c.5067_5079delinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant	34/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5067_5079delinsGGCCGTGGAAGAA	p.Val1692Glu	missense_variant	35/40	1	NM_000257.4	ENSP00000347507	P1
	ENST00000557368.1			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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 24, 2014

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505033; hg19: chr14-23884916;