chr14-23417270-C-T

Variant names:

• chr14-23417270-C-T
• rs876657884
• NM_000257.4:c.4402G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):​c.4402G>A​(p.Glu1468Lys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 7.61

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.918
• PP5: Variant 14-23417270-C-T is Pathogenic according to our data. Variant chr14-23417270-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4402G>A	p.Glu1468Lys	missense_variant	Exon 32 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4402G>A	p.Glu1468Lys	missense_variant	Exon 31 of 39		NP_001393933.1
MHRT	NR_126491.1	n.710C>T		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4402G>A	p.Glu1468Lys	missense_variant	Exon 32 of 40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Sep 14, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27054166, 27247418, 26656175, 27737317) -

Hypertrophic cardiomyopathy Pathogenic:1

Jun 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1468 of the MYH7 protein (p.Glu1468Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26656175, 27247418, 27737317, 30297972; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 235033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Oct 31, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.4402G>A (p.Glu1468Lys) results in a conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251430 control chromosomes (gnomAD). c.4402G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Mattos_2016, Bottillo_2016, Homburger_2016, Miller_2019) and has been reported to segregate with the disease phenotype within affected families, although multiple unaffected family members were also reported with the variant, suggesting a reduced penetrance (Mattos_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26656175, 30297972, 27247418, 27737317, 31199839). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Mar 04, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1468K variant (also known as c.4402G>A), located in coding exon 30 of the MYH7 gene, results from a G to A substitution at nucleotide position 4402. The glutamic acid at codon 1468 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy and has been shown to segregate with disease in several families (Bottillo I et al. Gene, 2016 Feb;577:227-35; Mattos BP et al. Arq. Bras. Cardiol., 2016 Sep;107:257-265; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; external communication; Ambry internal data). However, a number of relatives positive for this alteration were reportedly unaffected, suggesting incomplete penetrance. 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant and digenic HCM reported. Recessive for myosin storage myopathy (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. HCM associated with MYH7 variants is known to have reduced penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail domain (PDB). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Glu1468Gln) has been classified as a VUS in one HCM patient (PMID: 30297972) and has one VUS entry in ClinVar (no clinical information provided). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in three unrelated HCM families (PMID: 27737317) and has two likely pathogenic entries (cardiovascular phenotype and HCM) and one VUS entry (no clinical information provided) in ClinVar. (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has segregated with HCM in two unrelated families with a total of five meioses. The variant had incomplete penetrance within the two families (PMID: 27737317). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified Uncertain:1

Mar 18, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1468Lys (c.4402G>A) in the MYH7 gene. The variant is novel. This is a non-conservative amino acid change with an acidic polar glutamic acid replaced with a basic polar lysine. The glutamic acid at position 1468 is completely conserved across species. In silico analysis with PolyPhen predicts the variant to be probably damaging with a score of 0.990. Mutation Taster predicts this variant to be disease causing with a score of 56. No other disease-causing variants have been reported at this or nearby codons (+/- 5 codons). The variant was not observed in 200 presumed healthy individuals of Caucasian and African-American ancestry at GeneDx. There is no variation at codon 1468 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 6/20/13. There is also no variant at codon 1468 in 1000 genomes or dbSNP (as of 6/20/13). There is currently insufficient data available on the variant to determine if it causes cardiomyopathy, however the data that is available does suggest it may be pathogenic. Segregation analysis could help clarify the status of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.53		Gain of ubiquitination at E1468 (P = 0.001);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.95

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: rs876657884; hg19: chr14-23886479;