ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.5655G>A (p.Ala1885=)
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.
Pathogenic(8); Likely pathogenic(3); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.5655G>A (p.Ala1885=)
Variation ID: 378215 Accession: VCV000378215.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23414007 (GRCh38) [ NCBI UCSC ] 14: 23883216 (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 Mar 8, 2017 May 1, 2024 Dec 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.5655G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Ala1885= synonymous NC_000014.9:g.23414007C>T NC_000014.8:g.23883216C>T NG_007884.1:g.26655G>A LRG_384:g.26655G>A LRG_384t1:c.5655G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000014.9:23414006:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
3600 | 4857 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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) |
criteria provided, single submitter
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Mar 22, 2023 | RCV000443632.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000540471.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 30, 2023 | RCV001526294.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2023 | RCV001537863.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2019 | RCV002348150.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2023 | RCV003333065.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2023 | RCV003333063.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2023 | RCV003333062.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2023 | RCV003333064.1 | |
MYH7-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2020 | RCV004545880.1 |
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
Help
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
Help
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
(Mar 22, 2023)
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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: SCV000513813.5
First in ClinVar: Mar 08, 2017 Last updated: Apr 01, 2023 |
Comment:
Identified as a de novo variant in a young adult with congenital myopathy and left bundle branch block (Fiorillo et al., 2016); Not observed at … (more)
Identified as a de novo variant in a young adult with congenital myopathy and left bundle branch block (Fiorillo et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); RNA studies have shown that this variant damages the natural splice donor site in intron 38, leading to in-frame skipping of exon 38 and resulting in a truncated protein product (Pajusalu et al., 2016; Fiorillo et al., 2016); This variant is associated with the following publications: (PMID: 26782017, 27387980, 33240318, 34135346, 33333461, 30794915, 36264615, 34363016) (less)
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Likely pathogenic
(Nov 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001754768.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice … (more)
The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice site for this exon. Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID: 26782017, 27387980). This variant has been reported in two individuals: one with early onset muscular weakness and fiber-type disproportion (PMID: 26782017) and a second patient with an early infantile onset of respiratory muscle impairment and left bundle branch block (PMID: 27387980). Notably, several patients with different genomic variants but identical exon 38 skipping (c.5655+1G>A, c.5655+5G>C) also demonstrate cardiac manifestations in the form of dilated cardiomyopathy and left ventricular non-compaction (PMID: 30794915, 27387980). This variant has been observed at an ultra-low frequency in the general population (gnomAD database 3/251,438). For these reasons, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Dec 27, 2023)
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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: SCV000623748.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 1885 of the MYH7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 1885 of the MYH7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYH7 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs753392652, gnomAD 0.003%). This variant has been observed in individual(s) with MYH7-related myopathy (PMID: 26782017, 27387980). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 378215). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of skipping of exon 38, but is expected to preserve the integrity of the reading-frame (PMID: 26782017, 27387980). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838097.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Myopathy, myosin storage, autosomal recessive
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041159.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Myosin storage myopathy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041263.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1S
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041466.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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MYH7-related skeletal myopathy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041499.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041469.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Likely pathogenic
(Jan 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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MYH7-related disease
Affected status: unknown
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183373.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PP5
Geographic origin: Brazil
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Uncertain significance
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004359497.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This synonymous variant alters the conserved c.G at the last nucleotide of exon 38 of the MYH7 gene and has been shown to cause aberrant … (more)
This synonymous variant alters the conserved c.G at the last nucleotide of exon 38 of the MYH7 gene and has been shown to cause aberrant splicing and in-frame skipping of exon 38 (p.1854_1885del) (PMID: 26782017, 27387980, 30794915). This variant is expected to result in the expression of a truncated protein missing a part of LMM domain, which is a C-terminal tail region that forms the thick filament backbone and interacts with other proteins (PMID: 25125180). This variant has been reported in two individuals affected with congenital myopathy without cardiac involvement (PMID: 26782017, 33333461) and in an individual affected with congenital myopathy with cardiac left bundle block (PMID: 27387980). The variant occurred de novo in two carriers (PMID: 26782017, 27387980). This variant has not been reported in individuals affected with hypertrophic cardiomyopathy. This variant has been identified in 3/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant may have adverse structural impact by disrupting RNA splicing, but its impact on MYH7 protein function remains unknown. While this variant has been observed in individuals with congenital myopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant hypertrophic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004842970.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice … (more)
The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice site for this exon. Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID: 26782017, 27387980). This variant has been reported in two individuals: one with early onset muscular weakness and fiber-type disproportion (PMID: 26782017) and a second patient with an early infantile onset of respiratory muscle impairment and left bundle branch block (PMID: 27387980). Notably, several patients with different genomic variants but identical exon 38 skipping (c.5655+1G>A, c.5655+5G>C) also demonstrate cardiac manifestations in the form of dilated cardiomyopathy and left ventricular non-compaction (PMID: 30794915, 27387980). This variant has been observed at an ultra-low frequency in the general population (gnomAD database 3/251,438). For these reasons, this variant has been classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 16, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002652975.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.5655G>A pathogenic mutation (also known as p.A1885A), located in coding exon 36 of the MYH7 gene, results from a G to A substitution at … (more)
The c.5655G>A pathogenic mutation (also known as p.A1885A), located in coding exon 36 of the MYH7 gene, results from a G to A substitution at nucleotide position 5655. This nucleotide substitution does not change the alanine at codon 1885. However, this change occurs in the last base pair of coding exon 36, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in multiple individuals with MYH7-related myopathies and reportedly arose de novo in three of the cases (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91; Invitae pers. comm.; GeneDx pers. comm.; Ambry internal data). RNA studies indicate that this variant disrupts normal splicing, leading to the in-frame skipping of exon 38 (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91). Internal structural assessment suggests that the predicted resulting in-frame deletion would disrupt the coiled-coil formation in the Assembly Competency Domain, which appears to be critical for thick filament assembly (Sohn RL et al. J. Mol. Biol., 1997 Feb;266:317-30; Delorenzi M et al. Bioinformatics, 2002 Apr;18:617-25; Gruber M et al. J. Struct. Biol., 2006 Aug;155:140-5; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for MYH7-related skeletal myopathy; however, the association with cardiomyopathy is unclear. (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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The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort. | Natera-de Benito D | Pediatric neurology | 2021 | PMID: 33333461 |
Common pathogenic mechanism in patients with dropped head syndrome caused by different mutations in the MYH7 gene. | Surikova Y | Gene | 2019 | PMID: 30794915 |
MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients. | Fiorillo C | Orphanet journal of rare diseases | 2016 | PMID: 27387980 |
De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion. | Pajusalu S | Neuromuscular disorders : NMD | 2016 | PMID: 26782017 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Structural implications of β-cardiac myosin heavy chain mutations in human disease. | Colegrave M | Anatomical record (Hoboken, N.J. : 2007) | 2014 | PMID: 25125180 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Comparative analysis of coiled-coil prediction methods. | Gruber M | Journal of structural biology | 2006 | PMID: 16870472 |
An HMM model for coiled-coil domains and a comparison with PSSM-based predictions. | Delorenzi M | Bioinformatics (Oxford, England) | 2002 | PMID: 12016059 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
A 29 residue region of the sarcomeric myosin rod is necessary for filament formation. | Sohn RL | Journal of molecular biology | 1997 | PMID: 9047366 |
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Text-mined citations for rs753392652 ...
HelpRecord last updated Jun 02, 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.