rs1064792935

Positions:

• chr14-23420200-G-GCCTCCAGCTCCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000257.4(MYH7):​c.3370_3371insAGGAGCTGGAGG​(p.Glu1120_Glu1123dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1124A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH7 NM_000257.4 inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 6.04

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000257.4.
• PP5: Variant 14-23420200-G-GCCTCCAGCTCCT is Pathogenic according to our data. Variant chr14-23420200-G-GCCTCCAGCTCCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.3370_3371insAGGAGCTGGAGG	p.Glu1120_Glu1123dup	inframe_insertion	27/40	ENST00000355349.4
MYH7	NM_001407004.1	c.3370_3371insAGGAGCTGGAGG	p.Glu1120_Glu1123dup	inframe_insertion	26/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.3370_3371insAGGAGCTGGAGG	p.Glu1120_Glu1123dup	inframe_insertion	27/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2017

- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with MYH7-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 407195). This variant is not present in population databases (ExAC no frequency). This variant, c.3359_3370dup, results in the insertion of 4 amino acid(s) to the MYH7 protein (p.Glu1120_Glu1123dup), but otherwise preserves the integrity of the reading frame. -

MYH7-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The MYH7 c.3359_3370dup12 variant is predicted to result in an in-frame duplication (p.Glu1120_Glu1123dup). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/407195/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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: rs1064792935; hg19: chr14-23889409;