chr14-23415174-G-T

Variant names:

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

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>A​(p.Gln1794Lys) 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. Q1794E) 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:2 U:1
• 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-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43067.
• 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, 0.886
• PP5: Variant 14-23415174-G-T is Pathogenic according to our data. Variant chr14-23415174-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43066.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5380C>A	p.Gln1794Lys	missense_variant	Exon 37 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5380C>A	p.Gln1794Lys	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>A	p.Gln1794Lys	missense_variant	Exon 37 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5380C>A	p.Gln1794Lys	missense_variant	Exon 37 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5380C>A	p.Gln1794Lys	missense_variant	Exon 36 of 39			ENSP00000519071.1
ENSG00000258444	ENST00000557368.1	n.-165G>T		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:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1794 of the MYH7 protein (p.Gln1794Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 22464770, 26573135, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 43066). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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. -

Nov 23, 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.Gln1794Lys variant in MYH7 has been identified in 5 individuals with HCM ( Xu 2015, Walsh 2017, GeneDx pers. comm., LMM data) and was found to have occurre d apparently de novo in one individual with childhood onset HCM (GeneDx pers. co mm.). It was absent from large population studies but has been reported in ClinV ar (Variation ID # 43066). The p.Gln1794Glu variant in MYH7 has also been identi fied in individuals with HCM, however, the clinical significance of this variant is currently uncertain. Glutamine (Gln) at position 1794 is highly conserved in mammals and across evolutionarily distant species and the change to lysine (Lys ) was predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clinical significance. This tool's pathogenic prediction is estimated to be corr ect 94% of the time (Jordan 2011). In summary, although additional studies are r equired to fully establish its clinical significance, this variant meets criteri a to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Cri teria applied: PS4_Moderate, PP3, PM2, PM6. -

not provided Pathogenic:1

May 10, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q1794K variant in the MYH7 gene has reported previously in association with HCM (Xu et al., 2015; Walsh et al., 2017), although specific clinical details were not provided. In addition, Q1794K has been identified as an assumed de novo occurrence in one individual, and observed independently of additional cardiogenetic variants in another individual referred for cardiomyopathy genetic testing at GeneDx. The Q1794K variant is not observed in large population cohorts (Lek et al., 2016). The Q1794K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Thus, Q1794K in the MYH7 gene is interpreted as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.50		Gain of ubiquitination at Q1794 (P = 0.009);
MVP		0.97
MPC		1.7
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.95
Mutation Taster		=2/98	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;