14-23428505-C-T

Variant names:

• chr14-23428505-C-T
• rs606231324
• NM_000257.4:c.1573G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):​c.1573G>A​(p.Glu525Lys) 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. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.67
• Publications: 15 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000257.4
• 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 myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 14-23428505-C-T is Pathogenic according to our data. Variant chr14-23428505-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132925.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.1573G>A	p.Glu525Lys	missense_variant	Exon 15 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.1573G>A	p.Glu525Lys	missense_variant	Exon 14 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.1573G>A	p.Glu525Lys	missense_variant	Exon 15 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.1573G>A	p.Glu525Lys	missense_variant	Exon 15 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.1573G>A	p.Glu525Lys	missense_variant	Exon 14 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1S Pathogenic:3

Jul 11, 2019

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1573G>A, p.Glu525Lys missense variant identified in the MYH7 gene has been reported as de novo in at least two patients with infantile-onset dilated cardiomyopathy [PMID:27532257; PMID: 22464770]. This variant is not reported in gnomAD database indicating this is a rare variant. This variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease [PMID:27532257]. Based on the available evidence, the p.Glu525Lys variant in the MYH7 gene is classified as likely pathogenic. -

-

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant is absent from gnomAD (both v2 and v3). - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in individuals with dilated cardiomyopathy. In several individuals, the variant had been shown to be de novo (ClinVar, PMID: 22464770, PMID: 29892087). - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). Additional information: - 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). - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). - The condition associated with this gene has incomplete penetrance (PMID: 29300372). - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. - This variant is heterozygous. - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). -

Nov 08, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jan 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a South Indian family with four members diagnosed with HCM between 3-18 years of age and all four affected individuals were heterozygous for this variant and the S215L variant in the TPM1 gene, and homozygous for the D896N variant in the MYH7 gene (PMID: 25607779); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 24503780, 29300372, 22464770, 34935411, 33500567, 25607779) -

Jun 21, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Found to be de novo in a male infant diagnosed at 2 weeks of age with DCM/LVNC at our center. There is no known family history of DCM/LVNC. Genetic testing was conducted through the Invitae laboratory and included 86 genes associated with heritable cardiomyopathies. The following genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACADVL, ACTC1, ACTN2, AGL, ALMS1, ANKRD1, BAG3, CACNA1C, CALR3, CAV3, CHRM2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, GAA, GATA4, GATA6, GATAD1, GLA, HCN4, ILK, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RBM20, RYR2, SCN5A, SGCD, SLC22A5, TAZ, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL. The following genes were evaluated for sequence changes only: SDHA Both parents subsequently tested negative for the variant at Invitae, with paternity molecularly confirmed. p.Glu525Lys (E525K; c.1573G>A) in exon 15 of the MYH7 gene (NM_000257.3) Chromosome position: 14:23897714 C / T Based on the information reviewed below, we classify it as Likely Pathogenic, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk relatives. p.Glu525Lys has been reported as arising de novo in one individual affected with dilated cardiomyopathy and tested at the Laboratory for Molecular Medicine (PMID: 22464770, Lakdawala et al. 2012). This is a nonconservative amino acid change, resulting in the replacement of a negatively charged Glutamic Acid with a positively charged Lysine. Glutamic Acid at this location is absolutely conserved across ~100 vertebrate species for which we have data, as are the adjacent residues. Invitae reports that algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. An analysis by Homburger et al. (2016), specific to HCM, identifies this residue as being in a portion of the myosin head which is enriched for pathogenic variation in surface residues in the pre-stroke conformation. In total the variant has not been seen in >140,000 individuals from publicly available population datasets. Variation at this codon has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is 50x sequencing coverage for almost all ExAC participants at this site. It is also not seen in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which expands upon ExAC to include variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi Jewish descent. -

Familial cardiomyopathy Pathogenic:1

-

Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:1

-

Molecular Genetics Lab, CHRU Brest

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction cardiomyopathy Pathogenic:1

Jun 04, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:1

Dec 02, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu525Lys variant in MYH7 has been reported as a de novo variant in at least 3 individuals with dilated cardiomyopathy (Lakdawala 2012 PMID: 22464770, LMM data, Invitae data, pers comm.). It was absent from large population studies. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016 PMID: 19864899). This variant has also been reported in ClinVar (Variation ID 132925). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant cardiomyopathy. ACMG/AMP Criteria applied: PS2_VeryStrong, PM1, PM2_Supporting, PS4_Supporting. -

Hypertrophic cardiomyopathy Pathogenic:1

Apr 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 132925). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 22464770; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 525 of the MYH7 protein (p.Glu525Lys). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.94
MutPred		0.78		Gain of catalytic residue at I530 (P = 8e-04);
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.92
gMVP		0.99
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: rs606231324; hg19: chr14-23897714;