chr14-23415174-G-C

Variant names:

• chr14-23415174-G-C
• rs397516247
• NM_000257.4:c.5380C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.5380C>G​(p.Gln1794Glu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1794K) has been classified as Likely pathogenic.

• 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:3
• Conservation: PhyloP100: 7.82
• Publications: 8 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

ENSG00000258444 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23415174-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43066.
• 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, 0.919
• PP5: Variant 14-23415174-G-C is Pathogenic according to our data. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067. Variant chr14-23415174-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43067.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5380C>G	p.Gln1794Glu	missense_variant	Exon 37 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5380C>G	p.Gln1794Glu	missense_variant	Exon 36 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5380C>G	p.Gln1794Glu	missense_variant	Exon 37 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5380C>G	p.Gln1794Glu	missense_variant	Exon 37 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5380C>G	p.Gln1794Glu	missense_variant	Exon 36 of 39			ENSP00000519071.1
ENSG00000258444	ENST00000557368.1	n.-165G>C		upstream_gene_variant		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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Jun 28, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 01, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Uncertain:1

May 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28606303, 20474083, 22464770, 27532257, 24503780, 37652022) -

Hypertrophic cardiomyopathy Uncertain:1

May 20, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it 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 (PMID: 22464770). ClinVar contains an entry for this variant (Variation ID: 43067). This variant is not present in population databases (rs397516247, ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 1794 of the MYH7 protein (p.Gln1794Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.45		Loss of MoRF binding (P = 0.0393);
MVP		0.97
MPC		1.6
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.72
gMVP		0.92
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: rs397516247; hg19: chr14-23884383;