ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu)
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
-
NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu)
Variation ID: 42948 Accession: VCV000042948.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q11.2 14: 23422291 (GRCh38) [ NCBI UCSC ] 14: 23891500 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 26, 2017 Feb 20, 2024 Aug 25, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000257.4:c.3134G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg1045Leu missense NC_000014.9:g.23422291C>A NC_000014.8:g.23891500C>A NG_007884.1:g.18371G>T LRG_384:g.18371G>T LRG_384t1:c.3134G>T - Protein change
- R1045L
- Other names
- NM_000257.4(MYH7):c.3134G>T
- Canonical SPDI
- NC_000014.9:23422290:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
MYH7 | No evidence available | No evidence available |
GRCh38 GRCh37 |
3417 | 4600 |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (3) |
reviewed by expert panel
|
Aug 25, 2021 | RCV000629019.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 13, 2023 | RCV001188088.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2018 | RCV001258092.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2022 | RCV001703459.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2022 | RCV002321503.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 23, 2021 | RCV002496541.8 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Aug 25, 2021)
|
reviewed by expert panel
Method: curation
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV001976477.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 … (more)
The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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; PP3. (less)
|
|
Likely pathogenic
(Dec 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059492.6
First in ClinVar: May 03, 2013 Last updated: Jul 04, 2020 |
Comment:
The p.Arg1045Leu variant in MYH7 has been identified in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives … (more)
The p.Arg1045Leu variant in MYH7 has been identified in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives from 3 families (Cann 2017, Walsh 2017, Invitae pers. comm., GeneDx pers. comm., LMM data). It has also been identified in 1 individual with HCM who carried an additional pathogenic variant in MYH7 (LMM data). This variant has also reported by other clinical laboratories in ClinVar (Variation ID#42948) and has been identified in 0.004% (4/113744) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg1045Cys) has been identified in individuals with HCM and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Moderate, PM5_Supporting. (less)
Number of individuals with the variant: 4
|
|
Likely pathogenic
(Sep 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
MYH7-related skeletal myopathy
Myosin storage myopathy Hypertrophic cardiomyopathy 1 Myopathy, myosin storage, autosomal recessive Congenital myopathy 4A, autosomal dominant Myosin storage myopathy Dilated cardiomyopathy 1S
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809753.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Likely pathogenic
(Oct 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208523.6
First in ClinVar: Feb 24, 2015 Last updated: Jan 21, 2023 |
Comment:
Reported in several individuals with HCM (Alfares et al., 2015; Cann et al., 2016; Walsh et al., 2015), and reported as p.(R1045L) (c.3134G>T) in another … (more)
Reported in several individuals with HCM (Alfares et al., 2015; Cann et al., 2016; Walsh et al., 2015), and reported as p.(R1045L) (c.3134G>T) in another individual with HCM (de Marvao et al., 2021); 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: 25611685, 27532257, 31447099, 27247418, 34542152, 34636345, 34503678, 27000522) (less)
|
|
Likely pathogenic
(Oct 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypertrophic cardiomyopathy 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434936.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene has been reported in at least three unrelated patients with hypertrophic cardiomyopathy (PMID 25611685, 26914223, 27247418) and … (more)
This c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene has been reported in at least three unrelated patients with hypertrophic cardiomyopathy (PMID 25611685, 26914223, 27247418) and is extremely rare in general population databases. A second variant in the same codon, p. Arg1045His was classified likely pathogenic by our laboratory. A third variant at this codon, p.Arg1045Cys was classified as likely pathogenic by expert panel in the Clinvar database, suggesting this arginine residue is critical for MYH7 protein function. Multiple lines of prediction algorithms support the deleterious effect of the c.3134G>T (p.Arg1045Leu) variant. Therefore, this c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene is classified as likely pathogenic. (less)
|
|
Likely pathogenic
(Dec 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002607568.2
First in ClinVar: Nov 29, 2022 Last updated: Apr 15, 2023 |
Comment:
The p.R1045L variant (also known as c.3134G>T), located in coding exon 23 of the MYH7 gene, results from a G to T substitution at nucleotide … (more)
The p.R1045L variant (also known as c.3134G>T), located in coding exon 23 of the MYH7 gene, results from a G to T substitution at nucleotide position 3134. The arginine at codon 1045 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in numerous hypertrophic cardiomyopathy cohorts and has been reported to segregate with disease in several families (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203; Sheikh N et al. Circulation, 2018 Sep;138:1184-1194; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). An alternate amino acid substitution at this position, p.R1045C, has also been reported in HCM cases (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8). This amino acid position is highly 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)
|
|
Likely pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001355056.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with leucine at codon 1045 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that … (more)
This missense variant replaces arginine with leucine at codon 1045 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27000522, 27532257, 29764897, 33495596, 33495597; ClinVar SCV001976477.1). Several of these individuals also carried variants in other genes associated with hypertrophic cardiomyopathy (ClinVar SCV001976477.1). It has been shown that this variant segregates with disease in 6 affected individuals across 3 families (ClinVar SCV001976477.1). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 35732239). This variant has been identified in 4/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg1045Cys, is considered to be disease-causing (ClinVar variation ID: 177753), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
Pathogenic
(Dec 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000749929.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1045 of the MYH7 protein (p.Arg1045Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1045 of the MYH7 protein (p.Arg1045Leu). This variant is present in population databases (rs397516178, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42948). 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%. This variant disrupts the p.Arg1045 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 20215591, 24793961, 26914223, 27247418, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
Integrated multi-omic characterization of congenital heart disease. | Hill MC | Nature | 2022 | PMID: 35732239 |
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank. | Park J | Human molecular genetics | 2022 | PMID: 34542152 |
Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy. | de Marvao A | Journal of the American College of Cardiology | 2021 | PMID: 34503678 |
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. | Tadros R | Nature genetics | 2021 | PMID: 33495596 |
Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion. | Sheikh N | Circulation | 2018 | PMID: 29764897 |
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 |
Phenotype-driven molecular autopsy for sudden cardiac death. | Cann F | Clinical genetics | 2017 | PMID: 27000522 |
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 |
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 |
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 |
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. | Hershberger RE | Circulation. Cardiovascular genetics | 2010 | PMID: 20215591 |
A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy. | Frisso G | Clinical genetics | 2009 | PMID: 19659763 |
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
Digesta retention and fibre digestion in brushtail possums, ringtail possums and rabbits. | Sakaguchi E | Comparative biochemistry and physiology. A, Comparative physiology | 1990 | PMID: 1976477 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/40ccb7f9-d0a7-4e61-9756-8fef5c463031 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs397516178 ...
HelpRecord last updated Mar 23, 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.