ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.5500G>A (p.Ala1834Thr)
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.
Uncertain significance(12); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.5500G>A (p.Ala1834Thr)
Variation ID: 43073 Accession: VCV000043073.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23415054 (GRCh38) [ NCBI UCSC ] 14: 23884263 (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 Jun 8, 2015 May 1, 2024 Oct 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.5500G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Ala1834Thr missense NC_000014.9:g.23415054C>T NC_000014.8:g.23884263C>T NG_007884.1:g.25608G>A LRG_384:g.25608G>A LRG_384t1:c.5500G>A - Protein change
- A1834T
- Other names
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- Canonical SPDI
- NC_000014.9:23415053: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Uncertain significance (1) |
criteria provided, single submitter
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Feb 25, 2015 | RCV000035968.14 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2022 | RCV000172041.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 24, 2022 | RCV000560402.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 21, 2017 | RCV000627131.10 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2023 | RCV000770468.16 | |
Benign (1) |
criteria provided, single submitter
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Nov 20, 2017 | RCV001115179.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2017 | RCV001109553.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 17, 2022 | RCV002345282.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2017 | RCV003320087.8 |
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
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
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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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Uncertain significance
(Feb 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059620.5
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The p.Ala1834Thr va riant in MYH7 has been identified by our laboratory in 1 Caucasian individual wi … (more)
Variant classified as Uncertain Significance - Favor Benign. The p.Ala1834Thr va riant in MYH7 has been identified by our laboratory in 1 Caucasian individual wi th HCM who carried a variant in another gene that was sufficient to explain thei r disease. This variant has also been identified in 4/66670 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs143362532). Alanine (Ala) at position 1834 is not conserved in mammals or ev olutionarily distant species and the change to threonine (Thr) was predicted to be benign using a computational tool clinically validated by our laboratory. Thi s tool's benign prediction is estimated to be correct 89% of the time (Jordan 20 11). In summary, while the clinical significance of the p.Ala1834Thr variant is uncertain, these data suggest that it is more likely to be benign. (less)
Number of individuals with the variant: 2
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Uncertain Significance
(Oct 27, 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: SCV004814349.1
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:
This missense variant replaces alanine with threonine at codon 1834 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with threonine at codon 1834 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). This variant has been identified in 14/250566 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 10
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Uncertain significance
(Oct 17, 2022)
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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: SCV002650177.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A1834T variant (also known as c.5500G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.A1834T variant (also known as c.5500G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5500. The alanine at codon 1834 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort and as a secondary cardiac variant in an exome cohort; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000054823.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 1
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Uncertain significance
(Apr 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747945.1
First in ClinVar: May 21, 2018 Last updated: May 21, 2018 |
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Uncertain significance
(Nov 20, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001266900.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Nov 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Myosin storage myopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001266899.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Nov 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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MYH7-related skeletal myopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001273136.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Jun 15, 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: SCV000583230.3
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Reported in at least one individual in association with HCM (Homburger et al., 2016); however, no further clinical details or segregation data were described; In … (more)
Reported in at least one individual in association with HCM (Homburger et al., 2016); however, no further clinical details or segregation data were described; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by several clinical laboratories, one of which reported this variant in one Caucasian individual with HCM who harbored a variant in another gene that was sufficient to explain their disease (ClinVar Variant ID# 43073; SCV000059620.5; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362, 23403236, 27247418, 26582918, 27535533) (less)
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Uncertain significance
(Aug 24, 2022)
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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: SCV000623741.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1834 of the MYH7 protein (p.Ala1834Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1834 of the MYH7 protein (p.Ala1834Thr). This variant is present in population databases (rs143362532, gnomAD 0.008%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 43073). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. (less)
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Uncertain significance
(Nov 16, 2022)
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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: SCV003817655.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Mar 24, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901911.2 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 01, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001339634.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with threonine at codon 1834 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with threonine at codon 1834 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). This variant has been identified in 14/250566 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (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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Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation. | Homburger JR | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 27247418 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Text-mined citations for rs143362532 ...
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.