ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.1012G>A (p.Val338Met)
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.1012G>A (p.Val338Met)
Variation ID: 164381 Accession: VCV000164381.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23429901 (GRCh38) [ NCBI UCSC ] 14: 23899110 (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 2, 2015 May 1, 2024 Sep 27, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.1012G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Val338Met missense NC_000014.9:g.23429901C>T NC_000014.8:g.23899110C>T NG_007884.1:g.10761G>A LRG_384:g.10761G>A LRG_384t1:c.1012G>A - Protein change
- V338M
- Other names
- p.V338M:GTG>ATG
- NM_000257.4(MYH7):c.1012G>A
- Canonical SPDI
- NC_000014.9:23429900: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
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Oct 9, 2018 | RCV000158778.3 | |
Likely pathogenic (3) |
reviewed by expert panel
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Sep 27, 2021 | RCV000792549.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 12, 2021 | RCV002345472.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(Sep 27, 2021)
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reviewed by expert panel
Method: curation
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV001976465.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
The NM_000257.4(MYH7):c.1012G>A (p.Val338Met) variant in MYH7 has been identified in at least 11 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry, pers. … (more)
The NM_000257.4(MYH7):c.1012G>A (p.Val338Met) variant in MYH7 has been identified in at least 11 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry, pers. comm.; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.), and at least in a presumably unaffected individual (<40 years old) with a family history of HCM (Valente 2013 PMID: 23690394; Captur 2014 PMID:25228707). This variant segregated with disease in 6 affected relatives with HCM from 3 families (PP1_Moderate, GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Moderate; PM2, PM1. (less)
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Likely pathogenic
(Oct 09, 2018)
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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: SCV000208713.8
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
The V338M likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy (Valente et al., 2013; Captur et al., 2014; Walsh … (more)
The V338M likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy (Valente et al., 2013; Captur et al., 2014; Walsh et al., 2017). This variant has also been classified as a likely pathogenic variant and reported to segregate with disease in multiple members from one family by another clinical laboratory in ClinVar (SCV000199244.4; Landrum et al., 2016). The V338M variant is not observed in large population cohorts (Lek et al., 2016). A missense variant in the same residue (V338A) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Furthermore, the V338M variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). However, the V338M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, V338M in the MYH7 gene is interpreted as a likely pathogenic variant. (less)
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Likely pathogenic
(Nov 20, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000199244.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The p.Val338Met variant in MYH7 has been identified by our laboratory in 2 indiv iduals with HCM and segregated with disease in 5 affected relatives … (more)
The p.Val338Met variant in MYH7 has been identified by our laboratory in 2 indiv iduals with HCM and segregated with disease in 5 affected relatives from 1 famil y. Of note, affected individuals are reported to have varying ages of onset (age 3 - 50's). This variant was also identified in 2 teenagers with early signs of left ventricular wall thickening and in 3 asymptomatic obligate carriers. This v ariant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong evidence for or against an impac t to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Val338Met variant is likely pathogeni c. (less)
Number of individuals with the variant: 19
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Pathogenic
(Jan 29, 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: SCV000931853.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 338 of the MYH7 protein (p.Val338Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 338 of the MYH7 protein (p.Val338Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23690394, 27247418, 27532257, 32746448; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164381). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jul 12, 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: SCV002620615.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.V338M variant (also known as c.1012G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.V338M variant (also known as c.1012G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide position 1012. The valine at codon 338 is replaced by methionine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been detected in several individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing, and has shown some segregation with disease (Ho CY et al. Circ Cardiovasc Imaging, 2013 May;6:415-22; Captur G et al. Circ Cardiovasc Imaging. 2014;7:863-71; Homburger JR et al. Proc Natl Acad Sci USA. 2016;113(24):6701-6; Walsh R et al. Genet Med. 2017;19(2):192-203; Chida A et al. Heart Vessels. 2017 Jun;32(6):700-707; Mademont-Soler I et al. PLoS One. 2017 Aug;12(8):e0181465). In addition, this alteration has been detected by an outside laboratory in two probands reported to have HCM, and was reported to segregate with disease in multiple affected individuals from one family (LMM pers. comm.). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Apr 17, 2013)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280291.1
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
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.Val338Met (c.1012G>A) in MYH7. We have seen this variant in a family with HCM and it was present in multiple affected family members. The variant has been seen in a total of two unrelated HCM case (including the family in our center). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The valine at codon 338 is highly, though not completely, conserved across species; it is an isoleucine in platypus, chicken, and lizard. Neighboring amino acids are completely or highly conserved. We ere unable to find other variants reported in association with disease at this codon or nearby codons (+/- 5 positions). In total the variant has not been seen in ~6500 publicly available population datasets. There is no variation at codon 338 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 6th, 2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 6th, 2012). No published or laboratory control data is available. (less)
Number of individuals with the variant: 2
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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 variant burden and adverse outcomes in pediatric cardiomyopathy. | Burstein DS | Pediatric research | 2021 | PMID: 32746448 |
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. | Mademont-Soler I | PloS one | 2017 | PMID: 28771489 |
Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes. | Alamo L | eLife | 2017 | PMID: 28606303 |
The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers: Findings From the HCMNet Study. | Ho CY | JAMA cardiology | 2017 | PMID: 28241245 |
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 |
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 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy. | Captur G | Circulation. Cardiovascular imaging | 2014 | PMID: 25228707 |
Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy. | Valente AM | Circulation. Cardiovascular genetics | 2013 | PMID: 23690394 |
T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. | Ho CY | Circulation. Cardiovascular imaging | 2013 | PMID: 23549607 |
A novel custom resequencing array for dilated cardiomyopathy. | Zimmerman RS | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20474083 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0fb73aff-c7e0-4250-bc83-dd47e679755e | - | - | - | - |
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Text-mined citations for rs727503271 ...
HelpRecord last updated May 01, 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.