14-23419978-TCG-TGCTTCTT

Position:

• chr14-23419978-TCG-TGCTTCTT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000355349.4(MYH7):​c.3591_3592delinsAAGAAGC​(p.Asp1198ArgfsTer18) variant causes a frameshift 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. A1197A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH7 ENST00000355349.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.68

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 Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3591_3592delinsAAGAAGC	p.Asp1198ArgfsTer18	frameshift_variant	27/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3591_3592delinsAAGAAGC	p.Asp1198ArgfsTer18	frameshift_variant	26/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3591_3592delinsAAGAAGC	p.Asp1198ArgfsTer18	frameshift_variant	27/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1198fs variant in MYH7 has not been previously reported in individuals with cardiomyop athy. This variant deletes 2 bases and inserts 7, resulting in a frameshift, whi ch is predicted to alter the protein?s amino acid sequence beginning at position 1198 and to lead to a premature termination codon 18 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. It sho uld be noted that loss of function variants in the MYH7 gene are very rare and t herefore, their phenotypic spectrum is incompletely characterized. Emerging evid ence suggests that truncating variants in MYH7 have little/no effect on their ow n but result in severe and early onset disease when a second variant is present on the other copy of the gene (LMM unpublished data). In summary, while this var iant severely impacts the protein, its clinical significance is uncertain. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2022

This variant is present in population databases (rs755646089, gnomAD 0.002%). 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: 228908). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This sequence change creates a premature translational stop signal (p.Asp1198Argfs*18) 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. -

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: rs876657883; hg19: chr14-23889188;