ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2546T>C (p.Met849Thr)
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.2546T>C (p.Met849Thr)
Variation ID: 42914 Accession: VCV000042914.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23424902 (GRCh38) [ NCBI UCSC ] 14: 23894111 (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 Aug 11, 2024 May 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2546T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Met849Thr missense NC_000014.9:g.23424902A>G NC_000014.8:g.23894111A>G NG_007884.1:g.15760T>C LRG_384:g.15760T>C LRG_384t1:c.2546T>C - Protein change
- M849T
- Other names
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- Canonical SPDI
- NC_000014.9:23424901:A: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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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 |
3634 | 4908 | |
LOC126861898 | - | - | - | GRCh38 | - | 371 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV000788450.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 15, 2024 | RCV002426554.3 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2022 | RCV000035803.11 |
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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Likely pathogenic
(Mar 06, 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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Blueprint Genetics
Accession: SCV000927569.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Dilated Cardiomyopathy (DCM) Panel
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Likely pathogenic
(Apr 01, 2015)
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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: SCV000059454.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The p.Met849Thr variant in MYH7 has been reported in 1 individual with end-stage HCM (Garcia-Pavia) and was identified by our laboratory as a de novo … (more)
The p.Met849Thr variant in MYH7 has been reported in 1 individual with end-stage HCM (Garcia-Pavia) and was identified by our laboratory as a de novo occurrence in 1 Caucasian adult with HCM. This variant was absent from large population st udies. Methionine (Met) at position 849 is not well conserved in evolution; howe ver the change to threonine (Thr) was predicted to be pathogenic using a computa tional tool clinically validated by our laboratory. This tool's pathogenic predi ction is estimated to be correct 94% of the time (Jordan 2011). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Met849Thr variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 16, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001577616.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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). 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 C55"). ClinVar contains an entry for this variant (Variation ID: 42914). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 21896538, 26914223, 27532257, 29121657; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 849 of the MYH7 protein (p.Met849Thr). (less)
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Likely pathogenic
(May 15, 2024)
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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: SCV002742502.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.M849T variant (also known as c.2546T>C), located in coding exon 20 of the MYH7 gene, results from a T to C substitution at nucleotide … (more)
The p.M849T variant (also known as c.2546T>C), located in coding exon 20 of the MYH7 gene, results from a T to C substitution at nucleotide position 2546. The methionine at codon 849 is replaced by threonine, an amino acid with 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 variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) and showed co-segregation in an affected relative in one family; clinical details were limited in some cases (Garcia-Pavia P et al. Eur J Heart Fail, 2011 Nov;13:1193-201; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Chida A et al. Heart Vessels, 2017 Jun;32:700-707; Lorenzini M et al. J Am Coll Cardiol, 2020 08;76:550-559; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948). This variant was also detected in two individuals from HCM genetic testing cohorts (Walsh R et al. Genet Med, 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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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Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. | Lorenzini M | Journal of the American College of Cardiology | 2020 | PMID: 32731933 |
Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling. | Tobita T | Scientific reports | 2018 | PMID: 29386531 |
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy. | Dejgaard LA | Data in brief | 2017 | PMID: 28971120 |
Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes. | Alamo L | eLife | 2017 | PMID: 28606303 |
Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data. | Alejandra Restrepo-Cordoba M | Journal of cardiovascular translational research | 2017 | PMID: 28138913 |
Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy. | Chida A | Heart and vessels | 2017 | PMID: 27885498 |
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 |
Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. | Murphy SL | Journal of cardiovascular translational research | 2016 | PMID: 26914223 |
Genetic basis of end-stage hypertrophic cardiomyopathy. | Garcia-Pavia P | European journal of heart failure | 2011 | PMID: 21896538 |
Text-mined citations for rs397516156 ...
HelpRecord last updated Sep 29, 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.