14-23424878-G-T

Variant names:

• chr14-23424878-G-T
• rs397516158
• NM_000257.4:c.2570C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000257.4(MYH7):​c.2570C>A​(p.Thr857Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T857I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.51
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3631373).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2570C>A	p.Thr857Lys	missense	Exon 22 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.2570C>A	p.Thr857Lys	missense	Exon 21 of 39	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.2570C>A	p.Thr857Lys	missense	Exon 22 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.2570C>A	p.Thr857Lys	missense	Exon 22 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.2570C>A	p.Thr857Lys	missense	Exon 21 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 857 of the MYH7 protein (p.Thr857Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. 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 not expected to disrupt MYH7 protein function. This variant disrupts the p.Thr857 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28986455). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostCm	Benign	0.036
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.8
DANN	Benign	0.85
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.47	N
PhyloP100		-2.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.20
Sift	Benign	0.46	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.45		Loss of phosphorylation at T857 (P = 0.0076)
MVP		0.49
MPC		1.2
ClinPred		0.068	T
GERP RS		-0.82
Varity_R		0.072
gMVP		0.92
Mutation Taster		=72/28	polymorphism

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: rs397516158; hg19: chr14-23894087;