ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys)
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.4159G>A (p.Glu1387Lys)
Variation ID: 181244 Accession: VCV000181244.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23418220 (GRCh38) [ NCBI UCSC ] 14: 23887429 (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 May 29, 2016 May 1, 2024 Oct 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.4159G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Glu1387Lys missense NC_000014.9:g.23418220C>T NC_000014.8:g.23887429C>T NG_007884.1:g.22442G>A LRG_384:g.22442G>A LRG_384t1:c.4159G>A - Protein change
- E1387K
- Other names
- p.E1387K:GAG>AAG
- Canonical SPDI
- NC_000014.9:23418219: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.
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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
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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
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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 |
3599 | 4856 |
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) |
no assertion criteria provided
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Jul 7, 2014 | RCV000158638.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 24, 2023 | RCV000457747.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 4, 2021 | RCV000621684.10 | |
Uncertain significance (3) |
criteria provided, single submitter
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Oct 17, 2023 | RCV000766457.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 3, 2019 | RCV001109896.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001109893.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001109895.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV003320120.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2023 | RCV003486714.1 |
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
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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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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1S
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001267274.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Observation 1: Observation 2: |
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Uncertain significance
(Apr 27, 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: SCV001267275.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 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: SCV001267276.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 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: SCV001267277.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Oct 17, 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: SCV000208573.11
First in ClinVar: Feb 24, 2015 Last updated: Nov 25, 2023 |
Comment:
Identified in a family with HCM who also harbored c.(A934V) in cis (Wang et al., 2019); Not observed at significant frequency in large population cohorts … (more)
Identified in a family with HCM who also harbored c.(A934V) in cis (Wang et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28687478, 27247418, 21310275, 29121657, 34542152, 31638223) (less)
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Uncertain significance
(Apr 28, 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
Accession: SCV004239467.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(May 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433094.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Uncertain significance
(Jun 24, 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: SCV000546215.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181244). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 27247418, 29121657, 31638223). This variant is present in population databases (rs730880792, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1387 of the MYH7 protein (p.Glu1387Lys). (less)
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Uncertain significance
(Feb 04, 2021)
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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: SCV000736922.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.E1387K variant (also known as c.4159G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.E1387K variant (also known as c.4159G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4159. The glutamic acid at codon 1387 is replaced by lysine, an amino acid with similar properties. This aleratation has been detected in hypertrophic cardiomyopathy (HCM) cohorts; however, details were limited (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Viswanathan SK et al. PLoS One. 2017 Nov;12(11):e0187948). This variant co-occurred with a second MYH7 variant in a family with HCM (Wang B et al. Mol Med Rep. 2019 Dec;20(6):5229-5238). Another alteration affecting the same amino acid (p.E1387Q, c.4159G>C) has also been reported in association with HCM (O'Mahony C et al. Circ Arrhythm Electrophysiol, 2016 Jun;9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
(Jul 07, 2014)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280347.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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.Glu1387Lys (c.4159 G>A) in the MYH7 gene. The variant has been seen in at least one unrelated cases of HCM (not including this patient's family). No segregation data is available. GeneDx notes the variant is novel, however I found a report of the variant in a poster from the 2010 European Society of Cardiology meeting (Waldmuller et al 2010, Http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=P2062). I could not find a report of this variant in any publications by the same group. In the poster they report observing the variant in one of 20 patents with "suspected familial HCM" who underwent sequencing of 17 cardiomyopathy associated genes. Ancestry is not noted, however the report is by a German group. No segregation data was reported. The same group also reported on the variant, very likely from the same case, at the 2010 Congress of the German Human Genetics Society (Waldmuller et al 2010). It is not in ClinVar. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The glutamic acid at codon 1387 is completely conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with cardiomyopathy at nearby codons (p.Ala1379Thr (per the Seidman's database), p.Arg1382Gln, p.Arg1382Trp (per GeneDx report, referencing HGMD)). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 1387 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 23rd 2014).There is also no variation at this codon listed in dbSNP (as of July 24th, 2014). (less)
Number of individuals with the variant: 2
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932482.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952642.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Genetic analysis of monoallelic double MYH7 mutations responsible for familial hypertrophic cardiomyopathy. | Wang B | Molecular medicine reports | 2019 | PMID: 31638223 |
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
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 |
Text-mined citations for rs730880792 ...
HelpRecord last updated May 08, 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.