rs397516190

Variant names:

• chr14-23419910-TCTC-T
• rs397516190
• NM_000257.4:c.3658_3660delGAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4_Supporting PS4_Supporting PM2

This summary comes from the ClinGen Evidence Repository: The c.3658_3660del (p.Glu1220del) variant in MYH7 has been reported in 2 individuals with Ebstein anomaly (PS4_Supporting; Postma 2010 PMID:21127202; Bettinelli 2013 PMID 23956225; Partners LMM ClinVar SCV000059512.5). This variant segregated with Ebstein anomaly in 3 affected individuals from one family (Partners LMM ClinVar SCV000059512.5). While the expert panel waived the ACMG/AMP recommendation for demonstrating segregation in more than one family given that MYH7 is a well-established cardiomyopathy gene, its role in Ebstein anomaly is less established. Therefore, the expert panel felt that the PP1 pathogenic code should not be applied in this case given that all segregations came from one family. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 1220 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant is classified as uncertain significance for Ebstein anomaly in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM4_Supporting; PS4_ Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013921/MONDO:0009144/002

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH7 NM_000257.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 7.87
• Publications: 5 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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3658_3660delGAG	p.Glu1220del	conservative_inframe_deletion	Exon 27 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3658_3660delGAG	p.Glu1220del	conservative_inframe_deletion	Exon 26 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3658_3660delGAG	p.Glu1220del	conservative_inframe_deletion	Exon 27 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.3658_3660delGAG	p.Glu1220del	conservative_inframe_deletion	Exon 27 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.3658_3660delGAG	p.Glu1220del	conservative_inframe_deletion	Exon 26 of 39			ENSP00000519071.1

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: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Ebstein anomaly Uncertain:2

Jul 26, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An in-frame MYH7 c.3658_3660delGAG (p.Glu1220del) deletion variant was identified. This variant has been reported in one individual with Ebstein anomaly with left ventricular noncompaction (LVNC) and LV diastolic dysfunction (Postma AV et al., PMID: 21127202) and it is reported to segregate with Ebstein anomaly in one family with an affected father and 3 affected children (Bettinelli AL et al., PMID: 23956225). This variant causes a change in the length of the protein due to removal of a highly conserved amino acid (p.Glu1220) (Postma AV et al., PMID: 21127202). This variant has been reported in the ClinVar database by 4 submitters (including one submission by the ClinGen Cardiomyopathy Variant Curation Expert Panel, CMP-VCEP) in individuals with Ebstein anomaly or related cardiac conditions and is classified as uncertain/likely pathogenic (ClinVar Variation ID: 42968). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), and the recommendations provided by the ClinGen Inherited Cardiomyopathy Expert Panel (Kelly MA et al., PMID: 29300372) the clinical significance of this variant is uncertain at this time. -

Mar 22, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.3658_3660del (p.Glu1220del) variant in MYH7 has been reported in 2 individuals with Ebstein anomaly (PS4_Supporting; Postma 2010 PMID:21127202; Bettinelli 2013 PMID 23956225; Partners LMM ClinVar SCV000059512.5). This variant segregated with Ebstein anomaly in 3 affected individuals from one family (Partners LMM ClinVar SCV000059512.5). While the expert panel waived the ACMG/AMP recommendation for demonstrating segregation in more than one family given that MYH7 is a well-established cardiomyopathy gene, its role in Ebstein anomaly is less established. Therefore, the expert panel felt that the PP1 pathogenic code should not be applied in this case given that all segregations came from one family. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 1220 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant is classified as uncertain significance for Ebstein anomaly in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM4_Supporting; PS4_ Supporting. -

Left ventricular noncompaction Pathogenic:1

Jan 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Hypertrophic cardiomyopathy Uncertain:1

Oct 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. This variant, c.3658_3660del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Glu1220del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Ebstein anomaly (PMID: 21127202, 23956225). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42968). -

Cardiovascular phenotype Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3658_3660delGAG variant (also known as p.E1220del) is located in coding exon 25 of the MYH7 gene. This variant results from an in-frame GAG deletion at nucleotide positions 3658 to 3660. This results in the in-frame deletion of a glutamic acid at codon 1220. This variant has been detected in an individual with Ebstein anomaly, left ventricular noncompaction (LVNC) and left ventricular diastolic dysfunction, and was also reported to segregate in a family with Ebstein anomaly, ventricular septal defect, and left ventricular hypertrabeculation (Postma AV, Circ Cardiovasc Genet 2011 Feb; 4(1):43-50; Bettinelli AL, Am. J. Med. Genet. A 2013 Dec; 161A(12):3187-90). However, the association of MYH7 with Ebstein anomaly is not well established, and the etiology of LVNC is generally considered to be heterogeneous. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516190; hg19: chr14-23889119;