rs121913654

Variant names:

• chr14-23415176-A-G
• rs121913654
• NM_000257.4:c.5378T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-23415176-A-G
• chr14-23415176-A-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):​c.5378T>C​(p.Leu1793Pro) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L1793L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.10
• Publications: 16 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 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 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, 0.938
• PP5: Variant 14-23415176-A-G is Pathogenic according to our data. Variant chr14-23415176-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14123.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.5378T>C	p.Leu1793Pro	missense_variant	Exon 37 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5378T>C	p.Leu1793Pro	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.5378T>C	p.Leu1793Pro	missense_variant	Exon 37 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5378T>C	p.Leu1793Pro	missense_variant	Exon 37 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5378T>C	p.Leu1793Pro	missense_variant	Exon 36 of 39			ENSP00000519071.1
ENSG00000258444	ENST00000557368.1	n.-163A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000429 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 27, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); 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: 19138847, 28125727, 19336582, 28973424, 16684601)

Oct 08, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

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.Leu1793Pro (L1793P; c.5378 T>C) in the MYH7 gene, exon 37 Based on the data reviewed below, we consider this variant to be likely disease causing. As such it is suitable for predictive testing of family members. This variant is present in HGMD. It has been reported previously in 2 unrelated families. One of these was the original family reported to have myosin storage myopathy (MSM) by Cancilla et al. in 1971. A brother and sister in this family (ages 2 and 5 at initial publication) were both diagnosed with MSM, with skeletal muscle weakness from birth. The sister sat at 10 months and walked at 18-20 months. She later developed joint contractures of her limbs and severe scoliosis, and required ventilator assistance. She died of bronchopneumonia at age 25. Her younger brother crawled at 15 months, stood with support at 16 months, and walked without support at 20 months. He later developed scoliosis and had a tracheotomy at age 30. The ethnicity of the family is not stated. Dye et al. (2006) performed genetic testing on paraffin-embedded tissue taken from the sister at autopsy. No confirmatory testing was done in the brother. The parents appeared to be unaffected, but no genetic testing was performed for them. Uro-Coste et al. (2009) found this variant in a mother with myosin storage myopathy who developed proximal muscle weakness at age 30 (difficulty climbing stairs or raising her arms above her head). She also had weakness in her ankle dorsiflexors. By age 48 she was in a wheelchair, and her neck flexors and Achilles tendons were retracted. She later at age 51 developed hypertrophic cardiomyopathy. At age 53, exertional dyspnea led to oxygen therapy. Muscle biopsy showed high fiber size variation and increased interstitial fat and connective tissue. Type 2 fibers were hypotrophic and type 1 slow fibers were predominant. There was also fiber splitting and increased internal nuclei. The most prominent change was subsarcolemmal accumulation of hyaline material in type 1 fibers. Positive immunostaining was observed with antibodies to ventricular myosin. At age 58 she had volume-cycled nasal ventilatory support for 15 hours per day. The variant was also present in her daughter who presented at 3 months of age with heart failure due to left ventricular noncompaction. At age 10 the daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment, and she had some difficulty with heel-walking. The ethnicity of the family is not stated. The authors note that titin and other proteins interact with the myosin tail and could modulate phenotype. Residue 1793 is in the C-terminal extremity of the myosin heavy chain tail domain, or the “light meromyosin region”, which is where other variants shown to cause MSM are located (Dye et al. 2006, Uro-Coste et al. 2009, Armel & Leinwand 2009). This is a conservative amino acid change from a nonpolar leucine to a nonpolar proline in the light meromyosin (LMM) region of the myosin heavy chain tail. The leucine at codon 1793 is highly conserved (100% across 9 vertebrate species). In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Missense variants at nearby residues have also been listed in HGMD: Asp1792Gly, Gln1794Glu, and Glu1801Gly in association with dilated cardiomyopathy (HGMD professional version as of January 17, 2014). This potentially supports the functional importance of this region of the protein. By functional in vitro analysis, Armel and Leinwand (2009) showed that the L1793P mutation does not alter the secondary structure of the protein or the ability to for

Myosin storage myopathy Pathogenic:1

Apr 14, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Left ventricular noncompaction 5 Pathogenic:1

Apr 14, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hypertrophic cardiomyopathy Pathogenic:1

Sep 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to have conflicting or insufficient data to determine the effect on MYH7 protein function (PMID: 28125727, 19336582, 28973424). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu1793 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 24664454), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individuals affected with MYH7-related conditions (PMID: 16684601, 19138847, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14123). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1793 of the MYH7 protein (p.Leu1793Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.

Hypertrophic cardiomyopathy 1 Pathogenic:1

Apr 14, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		1.0
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: rs121913654; hg19: chr14-23884385;