rs193922387

Variant names:

• chr14-23424793-ATTC-A
• rs193922387
• NM_000257.4:c.2652_2654delGAA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4_Supporting PP5_Strong

The NM_000257.4(MYH7):​c.2652_2654delGAA​(p.Lys884del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4
• Conservation: PhyloP100: 6.02

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 120) in uniprot entity MYH7_HUMAN there are 91 pathogenic changes around while only 3 benign (97%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000257.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 14-23424793-ATTC-A is Pathogenic according to our data. Variant chr14-23424793-ATTC-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 36637.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2652_2654delGAA	p.Lys884del	disruptive_inframe_deletion	Exon 22 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2652_2654delGAA	p.Lys884del	disruptive_inframe_deletion	Exon 21 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2652_2654delGAA	p.Lys884del	disruptive_inframe_deletion	Exon 22 of 40	1	NM_000257.4	ENSP00000347507.3

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: Pathogenic:2 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:2

Oct 08, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys884del variant in MYH7 has been identified by other laboratories in at least 4 individuals with HCM, one of whom also had a variant in the TNNT2 gene ( GeneDx, Invitae, and Ambry personal communication; ClinVar Variation ID 36637). It was absent from large population studies. This variant is an in frame deletio n of a single amino acid at position 884. The variant falls within the head doma in of MYH7, where there is a statistically significant clustering of pathogenic variation. Furthermore, in-frame deletions of nearby amino acid residues (p.Glu8 75del, p.Lys876del, p.Glu883del) have been identified in individuals with cardio myopathy (Richard 2003, Alfares 2015, Walsh 2017), supporting that deletions in this region may generally not be tolerated. In summary, although additional stud ies are required to fully establish its clinical significance, this variant meet s criteria to be classified as likely pathogenic for autosomal dominant HCM. AC MG/AMP criteria applied: PM1, PM2, PM4, PS4_Supporting. -

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2652_2654del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Lys884del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36637). 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. -

Mar 22, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.2652_2654delGAA (p.Lys884del) variant in MYH7, also reported as c.2649_2651GAA[1], has been identified in 7 individuals with HCM (PS4_Moderate; Ambry pers comm; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with disease in 1 affected relative with HCM (Invitae pers. comm.). However, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). This variant is a deletion of 1 amino acid at position 884 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 hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PM4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Feb 22, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2652_2654delGAA variant (also known as p.K884del) is located in coding exon 20 of the MYH7 gene. This variant results from an in-frame GAA deletion at nucleotide positions 2652 to 2654. This results in the in-frame deletion of a lysine at codon 884. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Harper AR et al. Nat Genet, 2021 Feb;53:135-142; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799; Redin C et al. Eur J Med Genet, 2022 Dec;65:104627; Ambry internal data; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Mar 01, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.2652_2654delGAA (p.Lys884del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 121360 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2652_2654delGAA in individuals affected with Hypertrophic or Dilated Cardiomyopathy has been reported. Furthermore, no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Feb 24, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by three other clinical laboratories and as a likely pathogenic variant by another clinical laboratory (ClinVar Variant ID# 36637; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25611685, 27532257, 17095604, 12707239) -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922387; hg19: chr14-23894002;