rs45442096

Positions:

• chr14-23416102-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.4855G>A​(p.Glu1619Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.46

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:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 21) in uniprot entity MYH7_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000257.4
• 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). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. GenCC has associacion of the 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 14-23416102-C-T is Pathogenic according to our data. Variant chr14-23416102-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181268.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr14-23416102-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4855G>A	p.Glu1619Lys	missense_variant	34/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4855G>A	p.Glu1619Lys	missense_variant	33/39		NP_001393933.1
MHRT	NR_126491.1	n.363C>T		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4855G>A	p.Glu1619Lys	missense_variant	34/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2014

p.Glu1619Lys (GAA>AAA): c.4855 G>A in exon 34 of the MYH7 gene (NM_000257.2). The E1619K mutation in the MYH7 gene has been reported in one child with onset of cardiomyopathy at one month of age (Hershberger R et al., 2008; Rampersaud E et al., 2011). The father, paternal aunt, and two paternal cousins once removed were reported to have DCM, however these individuals were not available for genetic testing (Rampersaud E et al., 2011). E1619K is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The E1619 residue is highly conserved across species. Mutations in nearby residues (R1608P, R1634C) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Additionally, the E1619K mutation was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, E1619K in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2016

In summary this variant is a rare sequence change with an uncertain effect on protein function, without additional functional and/or genetic data, this variant has been classified as a variant of Uncertain Significance. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant has been reported in an individual affected with dilated cardiomyopathy. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 21483645). This variant was also reported in an individual affected with motor neuropathy (PMID: 27387980). However, one pathogenic allele was identified in the MYH7 gene, which suggests that this c.4855G>A substitution in MYH7 was not the primary cause of disease in this individual, ClinVar contains an entry for this variant (Variation ID: 181268). This variant is not present in population databases (ExAC no frequency) . This sequence change replaces glutamic acid with lysine at codon 1619 of the MYH7 protein (p.Glu1619Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		0.96	D
Vest4		0.92
MutPred		0.67		Gain of MoRF binding (P = 0.0057);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.91

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: rs45442096; hg19: chr14-23885311;