ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2585C>T (p.Ala862Val)
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.2585C>T (p.Ala862Val)
Variation ID: 36636 Accession: VCV000036636.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23424863 (GRCh38) [ NCBI UCSC ] 14: 23894072 (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 17, 2018 May 1, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2585C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Ala862Val missense NC_000014.9:g.23424863G>A NC_000014.8:g.23894072G>A NG_007884.1:g.15799C>T LRG_384:g.15799C>T LRG_384t1:c.2585C>T - Protein change
- A862V
- Other names
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- Canonical SPDI
- NC_000014.9:23424862:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 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 |
3604 | 4861 | |
LOC126861898 | - | - | - | GRCh38 | - | 368 |
Conditions - Germline
Condition
Help
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 (2) |
criteria provided, single submitter
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Jan 12, 2024 | RCV000464813.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 1, 2016 | RCV000590241.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 4, 2023 | RCV001184308.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 8, 2020 | RCV003133120.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 15, 2022 | RCV004018688.1 |
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
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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
(Jun 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696344.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The MYH7 c.2585C>T (p.Ala862Val) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome. This variant was … (more)
Variant summary: The MYH7 c.2585C>T (p.Ala862Val) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome. This variant was found in 4/121402 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYH7 variant (0.0010005). The variant was reported in an HCM-affected individual in the literature, without strong evidence for causality (Santos_2012). Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. (less)
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Uncertain significance
(Oct 08, 2020)
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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: SCV003817745.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Apr 25, 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: SCV001350257.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 862 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with valine at codon 862 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 individuals affected with hypertrophic cardiomyopathy (PMID: 22429680, 28408708, 32894683). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 34935411), in an individual affected with left ventricular noncompaction (PMID: 35026164), and in an individual affected with sudden death and suspected hypertrophic cardiomyopathy (PMID: 32361481). This variant has been identified in 8/282828 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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Uncertain significance
(Jan 12, 2024)
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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: SCV000546242.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 862 of the MYH7 protein (p.Ala862Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 862 of the MYH7 protein (p.Ala862Val). This variant is present in population databases (rs149576470, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 22429680, 28408708, 32894683, 34935411). ClinVar contains an entry for this variant (Variation ID: 36636). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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
(Sep 04, 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: SCV004818615.1
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 valine at codon 862 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with valine at codon 862 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 individuals affected with hypertrophic cardiomyopathy (PMID: 22429680, 28408708, 32894683). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 34935411), in an individual affected with left ventricular noncompaction (PMID: 35026164), and in an individual affected with sudden death and suspected hypertrophic cardiomyopathy (PMID: 32361481). This variant has been identified in 8/282828 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: 7
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Uncertain significance
(Apr 15, 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: SCV004943774.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.2585C>T (p.A862V) alteration is located in exon 22 (coding exon 20) of the MYH7 gene. This alteration results from a C to T substitution … (more)
The c.2585C>T (p.A862V) alteration is located in exon 22 (coding exon 20) of the MYH7 gene. This alteration results from a C to T substitution at nucleotide position 2585, causing the alanine (A) at amino acid position 862 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Feb 04, 2019)
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no assertion criteria provided
Method: research
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430822.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
The MYH7 Ala862Val variant has been previously identified in 1 HCM proband with apical hypertrophy who also carried another variant in MYBPC3 (Santos et al., … (more)
The MYH7 Ala862Val variant has been previously identified in 1 HCM proband with apical hypertrophy who also carried another variant in MYBPC3 (Santos et al., 2012). We identified this variant in a HCM proband of Lebanese descent, the variant was also found to segregate to 2 other affected family members (Ingles et al., 2017). The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at low frequency. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Computational tool SIFT, and PolyPhen-2 predict this variant to be benign, however MutationTaster predicts this variant to be "disease causing". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is located in a mutational hotspot (PM1), is rare in the general population (PM2) and in silico tools predict the variant to be deleterious (PP3) but it has been only been identified in 1 HCM proband without additional variants, therefore we classify MYH7 Ala862Val 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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The genetic architecture of pediatric cardiomyopathy. | Ware SM | American journal of human genetics | 2022 | PMID: 35026164 |
Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. | Khan RS | Journal of the American Heart Association | 2022 | PMID: 34935411 |
Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing. | Mattivi CL | Circulation. Genomic and precision medicine | 2020 | PMID: 32894683 |
Genetic variants of uncertain significance: How to match scientific rigour and standard of proof in sudden cardiac death? | Grassi S | Legal medicine (Tokyo, Japan) | 2020 | PMID: 32361481 |
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. | Ingles J | Circulation. Cardiovascular genetics | 2017 | PMID: 28408708 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Roadmap to determine the point mutations involved in cardiomyopathy disorder: a Bayesian approach. | Kumar A | Gene | 2013 | PMID: 23403236 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort. | Santos S | BMC medical genetics | 2012 | PMID: 22429680 |
Text-mined citations for rs149576470 ...
HelpRecord last updated Jun 17, 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.