ClinVar Genomic variation as it relates to human health
NM_002471.4(MYH6):c.1763A>C (p.Asp588Ala)
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(1); Benign(3); Likely benign(9)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002471.4(MYH6):c.1763A>C (p.Asp588Ala)
Variation ID: 155811 Accession: VCV000155811.85
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23398856 (GRCh38) [ NCBI UCSC ] 14: 23868065 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 6, 2015 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002471.4:c.1763A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002462.2:p.Asp588Ala missense NC_000014.9:g.23398856T>G NC_000014.8:g.23868065T>G NG_023444.1:g.14422A>C LRG_389:g.14422A>C LRG_389t1:c.1763A>C LRG_389p1:p.Asp588Ala - Protein change
- D588A
- Other names
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- Canonical SPDI
- NC_000014.9:23398855:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00060 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00130
The Genome Aggregation Database (gnomAD) 0.00153
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00169
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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MYH6 | - | - |
GRCh38 GRCh37 |
1828 | 2331 |
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
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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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Benign (1) |
no assertion criteria provided
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Dec 5, 2014 | RCV000143919.10 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Nov 24, 2020 | RCV000151221.27 | |
Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000172566.31 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000989183.17 | |
Benign (1) |
criteria provided, single submitter
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May 10, 2019 | RCV001798462.10 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 25, 2019 | RCV002408642.9 | |
MYH6-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Oct 26, 2020 | RCV004532623.1 |
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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Likely benign
(Jun 05, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000226269.5
First in ClinVar: Jun 28, 2015 Last updated: Apr 14, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Nov 24, 2020)
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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: SCV000697923.2
First in ClinVar: Jun 08, 2015 Last updated: Dec 07, 2020 |
Comment:
Variant summary: MYH6 c.1763A>C (p.Asp588Ala) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. … (more)
Variant summary: MYH6 c.1763A>C (p.Asp588Ala) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 252206 control chromosomes, predominantly at a frequency of 0.0032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 128 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1763A>C has been reported in the literature in individuals affected with Cardiomyopathy (Theis_2015, Lopes_2015, Christiansen_2016, Neubauer_2017, Mates_2018, Jaaskelainen_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign (1x), likely benign (6x) and uncertain significance (1x). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Apr 14, 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: SCV000513788.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 22955375, 8282798, 26085007, 20656787, 23396983, 28074886, 27789736, 23861362, 27760138, 27607113, 26284702, 21378987, 22194935, 19864899, 19808347, 15998695, … (more)
This variant is associated with the following publications: (PMID: 22955375, 8282798, 26085007, 20656787, 23396983, 28074886, 27789736, 23861362, 27760138, 27607113, 26284702, 21378987, 22194935, 19864899, 19808347, 15998695, 14573521, 8878443, 2969919) (less)
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Likely benign
(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: SCV000051407.1 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: 3
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Likely benign
(Sep 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740615.1
First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018 |
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Uncertain significance
(Aug 02, 2013)
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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: SCV000199079.4
First in ClinVar: Jan 30, 2015 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The Asp588Ala varia nt in MYH6 is present in 0.2% (19/8600) of European American chromosomes by the … (more)
Variant classified as Uncertain Significance - Favor Benign. The Asp588Ala varia nt in MYH6 is present in 0.2% (19/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs142992 009). It has also been reported in 1 individual with CHD (Granados-Riveron 2010) . Computational analyses (biochemical amino acid properties, conservation, Align GVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impac t to the protein. The variant?s population frequency suggests that it is more li kely benign but is too low to confidently rule out a disease-causing role. Addit ional information is needed to fully assess its clinical significance. (less)
Number of individuals with the variant: 3
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 14
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139405.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Aug 17, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884187.2
First in ClinVar: Jun 08, 2015 Last updated: Jan 26, 2021 |
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Benign
(May 10, 2019)
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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: SCV002043176.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Likely benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 14
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000287397.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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MYH6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004720370.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Mar 25, 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: SCV002716770.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Feb 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001149146.14
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
MYH6: BS1, BS2
Number of individuals with the variant: 1
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920957.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely benign
(-)
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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: SCV001930035.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(Dec 05, 2014)
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no assertion criteria provided
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000188793.2
First in ClinVar: Sep 07, 2014 Last updated: Feb 06, 2015 |
Number of individuals with the variant: 2
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Likely benign
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744409.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
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: SCV001953424.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971278.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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 basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy. | Jääskeläinen P | ESC heart failure | 2019 | PMID: 30775854 |
Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice. | Mates J | European journal of human genetics : EJHG | 2018 | PMID: 29511324 |
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. | Neubauer J | European journal of human genetics : EJHG | 2017 | PMID: 28074886 |
Impact of MYH6 variants in hypoplastic left heart syndrome. | Tomita-Mitchell A | Physiological genomics | 2016 | PMID: 27789736 |
Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting. | Christiansen SL | European journal of human genetics : EJHG | 2016 | PMID: 27650965 |
Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction. | Theis JL | Circulation. Cardiovascular genetics | 2015 | PMID: 26085007 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects. | Granados-Riveron JT | Human molecular genetics | 2010 | PMID: 20656787 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYH6 | - | - | - | - |
Text-mined citations for rs142992009 ...
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.