ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.5378T>C (p.Leu1793Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.5378T>C (p.Leu1793Pro)
Variation ID: 14123 Accession: VCV000014123.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23415176 (GRCh38) [ NCBI UCSC ] 14: 23884385 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 24, 2015 Feb 14, 2024 Feb 2, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.5378T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Leu1793Pro missense NC_000014.9:g.23415176A>G NC_000014.8:g.23884385A>G NG_007884.1:g.25486T>C LRG_384:g.25486T>C LRG_384t1:c.5378T>C LRG_384p1:p.Leu1793Pro P12883:p.Leu1793Pro - Protein change
- L1793P
- Other names
- p.L1793P:CTG>CCG
- Canonical SPDI
- NC_000014.9:23415175:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MYH7 | No evidence available | No evidence available |
GRCh38 GRCh37 |
3419 | 4604 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Apr 14, 2009 | RCV000015183.35 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 14, 2009 | RCV000015182.35 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2021 | RCV000158696.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2019 | RCV001207190.14 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 14, 2009 | RCV003320035.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017672.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001378532.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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 reported to have conflicting or insufficient data to determine the effect on MYH7 protein function (PMID: 28125727, 19336582, 28973424). 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. (less)
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Likely pathogenic
(Feb 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000208631.9
First in ClinVar: Feb 24, 2015 Last updated: May 03, 2018 |
Comment:
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; … (more)
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) (less)
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Likely pathogenic
(Oct 08, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280365.1
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
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 … (more)
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 form alpha-helical coiled coils compared to wildtype, but does decrease thermodynamic stability compared to wildtype. The L1793P mutation decreases the ability of LMM to assemble into an LMM rod (akin to forming thick filaments), presumably because of the increased instability of the molecule: Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly into filaments In total the variant has not been seen in ~6500 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes. Dye et al (2006) did not find it in 77 controls. This variant is listed in OMIM and based on this OMIM entry it was added to dbSNP as rs121913654 (as of March 26, 2014). (less)
Number of individuals with the variant: 3
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Pathogenic
(Apr 14, 2009)
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no assertion criteria provided
Method: literature only
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CONGENITAL MYOPATHY 7A, MYOSIN STORAGE, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035438.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) … (more)
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) identified a heterozygous c.5378T-C transition in exon 37 of the MYH7 gene, resulting in a leu1793-to-pro (L1793P) substitution in the light meromyosin (LMM) region of the myosin heavy chain tail. The sibs presumably had the disease because of gonadal mosaicism in 1 of the unaffected parents, although this could not be confirmed. In a mother with myosin storage myopathy who later developed hypertrophic cardiomyopathy (CMH1; 192600) and in her daughter who had early symptomatic left ventricular noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7. 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. Variant Function By functional analysis, Armel and Leinwand (2009) showed that the L1793P mutation did not differ in protein secondary structure or in the alpha-helical content compared to wildtype, but decreased thermodynamic stability compared to wildtype. The L1793P mutation altered the ability of LMM to assemble, presumably because of the increased instability of the molecule. Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly. (less)
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Pathogenic
(Apr 14, 2009)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035439.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) … (more)
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) identified a heterozygous c.5378T-C transition in exon 37 of the MYH7 gene, resulting in a leu1793-to-pro (L1793P) substitution in the light meromyosin (LMM) region of the myosin heavy chain tail. The sibs presumably had the disease because of gonadal mosaicism in 1 of the unaffected parents, although this could not be confirmed. In a mother with myosin storage myopathy who later developed hypertrophic cardiomyopathy (CMH1; 192600) and in her daughter who had early symptomatic left ventricular noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7. 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. Variant Function By functional analysis, Armel and Leinwand (2009) showed that the L1793P mutation did not differ in protein secondary structure or in the alpha-helical content compared to wildtype, but decreased thermodynamic stability compared to wildtype. The L1793P mutation altered the ability of LMM to assemble, presumably because of the increased instability of the molecule. Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly. (less)
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Pathogenic
(Apr 14, 2009)
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no assertion criteria provided
Method: literature only
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LEFT VENTRICULAR NONCOMPACTION 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035440.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) … (more)
In 1 of 2 sibs with autosomal dominant myosin storage congenital myopathy-7A (CMYP7A; 608358) originally reported by Cancilla et al. (1971), Dye et al. (2006) identified a heterozygous c.5378T-C transition in exon 37 of the MYH7 gene, resulting in a leu1793-to-pro (L1793P) substitution in the light meromyosin (LMM) region of the myosin heavy chain tail. The sibs presumably had the disease because of gonadal mosaicism in 1 of the unaffected parents, although this could not be confirmed. In a mother with myosin storage myopathy who later developed hypertrophic cardiomyopathy (CMH1; 192600) and in her daughter who had early symptomatic left ventricular noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7. 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. Variant Function By functional analysis, Armel and Leinwand (2009) showed that the L1793P mutation did not differ in protein secondary structure or in the alpha-helical content compared to wildtype, but decreased thermodynamic stability compared to wildtype. The L1793P mutation altered the ability of LMM to assemble, presumably because of the increased instability of the molecule. Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Myosin storage myopathy mutations yield defective myosin filament assembly in vitro and disrupted myofibrillar structure and function in vivo. | Viswanathan MC | Human molecular genetics | 2017 | PMID: 28973424 |
Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells. | Dahl-Halvarsson M | PloS one | 2017 | PMID: 28125727 |
Novel mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy. | Lamont PJ | Human mutation | 2014 | PMID: 24664454 |
Mutations in the beta-myosin rod cause myosin storage myopathy via multiple mechanisms. | Armel TZ | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19336582 |
Striking phenotypic variability in two familial cases of myosin storage myopathy with a MYH7 Leu1793pro mutation. | Uro-Coste E | Neuromuscular disorders : NMD | 2009 | PMID: 19138847 |
Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred. | Dye DE | Neuromuscular disorders : NMD | 2006 | PMID: 16684601 |
Familial myopathy with probable lysis of myofibrils in type I fibers. | Cancilla PA | Neurology | 1971 | PMID: 4104682 |
Text-mined citations for rs121913654 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.