ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.2003G>A (p.Arg668His)
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.
Likely pathogenic(1); Uncertain significance(6); Benign(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000256.3(MYBPC3):c.2003G>A (p.Arg668His)
Variation ID: 164090 Accession: VCV000164090.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47339715 (GRCh38) [ NCBI UCSC ] 11: 47361266 (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 Nov 14, 2015 Aug 25, 2024 Oct 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.2003G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg668His missense NC_000011.10:g.47339715C>T NC_000011.9:g.47361266C>T NG_007667.1:g.17988G>A LRG_386:g.17988G>A LRG_386t1:c.2003G>A LRG_386p1:p.Arg668His Q14896:p.Arg668His - Protein change
- R668H
- Other names
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- Canonical SPDI
- NC_000011.10:47339714: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00013
Exome Aggregation Consortium (ExAC) 0.00027
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
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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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3946 | 3965 |
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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 3, 2019 | RCV000151106.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 21, 2015 | RCV000201899.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 15, 2023 | RCV000621094.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2022 | RCV000628998.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2023 | RCV000766737.2 | |
Benign (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000988543.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 29, 2021 | RCV003531974.1 |
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
(Jan 12, 2015)
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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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Blueprint Genetics
Accession: SCV000264032.2
First in ClinVar: Feb 27, 2016 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 1
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Uncertain significance
(Sep 19, 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: SCV000617253.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
The R668H variant of uncertain significance in the MYBPC3 gene has been reported previously in association with HCM (Morner et al., 2003; Song et al., … (more)
The R668H variant of uncertain significance in the MYBPC3 gene has been reported previously in association with HCM (Morner et al., 2003; Song et al., 2005; Girolami et al., 2010). Initially, Morner et al., 2003 reported the R668H variant in two unrelated individuals with HCM, and was absent from 200 control alleles. Subsequently, this variant has been reported in at least one Chinese individual with HCM, and in one individual with HCM who also harbored additional variants in the MYH7 and MYBPC3 genes (Song et al., 2005; Girolami et al., 2010). Cann et al., 2016 reported this variant in one individual with HCM suspected on autopsy and in 27 relatives, three of which were reported to be clinically affected; detailed diagnostic criteria was not provided. This variant has also been reported in two unrelated individuals tested for cardiomyopathy at GeneDx. Additionally, the R668H variant was observed in 31/65808 alleles (~0.05%) from individuals of European (non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC).Although the R668H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. (less)
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Uncertain significance
(Sep 03, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198869.4
First in ClinVar: Feb 02, 2015 Last updated: Jul 03, 2020 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The p.Arg668His variant in MYBPC3 has been reported in at least 4 individuals with HCM (Morner 2003, … (more)
Variant classified as Uncertain Significance - Favor Benign. The p.Arg668His variant in MYBPC3 has been reported in at least 4 individuals with HCM (Morner 2003, Song 2005, Girolami 2010, Cann 2017); however, one of these individuals carried a second pathogenic variant in MYBPC3 that was sufficient to explain their disease (Girolami 2010, LMM data). The p.Arg668His variant has also been reported to segregate with cardiomyopathy in 2 families (Morner 2003, Cann 2017); however, detailed phenotypic information was not available. Furthermore, one clinically affected family member of a proband tested at our laboratory did not carry this variant (LMM data). The p.Arg668His variant has been identified in 0.026% (33/128360) of European chromosomes, including 1 homozygous individual, by gnomAD (http://gnomad.broadinstitute.org). This frequency is higher than expected for a pathogenic variant in the MYBPC3 gene. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain due to the presence of conflicting data, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, BS4, PP1, PP3. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Jul 21, 2015)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000256640.2
First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015 |
Comment:
This MYBPC3 Arg668His has been previously identified in multiple unrelated HCM cases (Morner S. et al., 2003; Song L. et al., 2005; Alfares AA. et … (more)
This MYBPC3 Arg668His has been previously identified in multiple unrelated HCM cases (Morner S. et al., 2003; Song L. et al., 2005; Alfares AA. et al., 2015). Familial segregation in one HCM family by Wang H. et al., (2008) found 3 HCM affecteds and 1 clinically unaffected to carry this variant. Similarly, familial investigation by Morner S. et al., (2003) identified clinically unaffected individuals to carry this MYBPC3 Arg668His variant. We have identified the MYBPC3 Arg668His variant in an HCM proband where two additional variants in MYBPC3 and MYH7 have also been observed in the family (Girolami F, et al., 2010). One of the additional variants (MYBPC3 Gln969*) is well described as disease-causing. Segregation analysis showed this MYBPC3 Arg668His variant to be present in one other clinically unaffected family member who carried an additional MYH7 Arg1079Gln variant (VUS). This variant is not observed in the 1000 genomes project (http://www.1000genomes.org/), but occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0002696. Furthermore, the MYBPC3 Arg668His has been identified in isolation in a heart study population (Bick AG, et al., 2012) and an HCM cohort (Alfares AA et al., 2015), but there is no further evidence provided in these studies to support a pathogenic role. Arginine (Arg) at position 668 is highly conserved across distantly related species and in silico tools SIFT and MutationTaster predict the impact of this variant to be "deleterious" and "disease-causing", respectively. No prediction is made by PolyPhen-HCM. Due to the possibility of incomplete disease penetrance in our family, limited segregation analysis due to small number of informative individuals, and co-occurrence with a MYBPC3 variant (Gln969*) that explains the disease phenotype, we classify this MYBPC3 Arg668His variant as one of "uncertain significance". (less)
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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 4
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138300.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Nov 29, 2021)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358696.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 668 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 668 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six unrelated individuals affected with hypertrophic cardiomyopathy as well as in eleven unaffected family members (PMID: 12818575, 15563892, 20359594, 25335496, 27000522). One of the affected individuals also carried a pathogenic truncation variant in the MYBPC3 gene that could explain the observed phenotype (PMID: 25335496). This variant occurs at an appreciable frequency in the general population and has been identified in 34/280486 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Sep 07, 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: SCV000749908.6
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 164090). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data … (more)
ClinVar contains an entry for this variant (Variation ID: 164090). 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 disrupts the p.Arg668 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 21302287), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12818575, 15563892, 20359594, 25335496, 28790153). This variant is present in population databases (rs727503191, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 668 of the MYBPC3 protein (p.Arg668His). (less)
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Uncertain significance
(Feb 15, 2023)
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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: SCV000740000.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R668H variant (also known as c.2003G>A), located in coding exon 21 of the MYBPC3 gene, results from a G to A substitution at nucleotide … (more)
The p.R668H variant (also known as c.2003G>A), located in coding exon 21 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2003. The arginine at codon 668 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals reported to have hypertrophic cardiomyopathy (HCM) (Mörner S et al. J Mol Cell Cardiol. 2003;35:841-9; Song L et al. Clin Chim Acta. 2005;351:209-16; Wang H et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2008;36:1059-62; Girolami F et al. J Am Coll Cardiol. 2010;55:1444-53), and also in a sudden cardiac death case (Cann F et al. Clin Genet. 2016 Mar). Family studies have identified this variant in some reportedly affected members, but also multiple unaffected family members, and this alteration has been reported to co-occur with alterations in other cardiac-related genes in one family (Mörner S et al. J Mol Cell Cardiol. 2003;35:841-9; Wang H et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2008;36:1059-62; Girolami F et al. J Am Coll Cardiol. 2010;55:1444-53; Cann F et al. Clin Genet. 2016 Mar). 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
(Oct 26, 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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199329.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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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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Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. | Burns C | Circulation. Cardiovascular genetics | 2017 | PMID: 28790153 |
Phenotype-driven molecular autopsy for sudden cardiac death. | Cann F | Clinical genetics | 2017 | PMID: 27000522 |
Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. | Wessels MW | European journal of human genetics : EJHG | 2015 | PMID: 25335496 |
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. | Bick AG | American journal of human genetics | 2012 | PMID: 22958901 |
Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy. | Roncarati R | Journal of cellular physiology | 2011 | PMID: 21302287 |
Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. | Girolami F | Journal of the American College of Cardiology | 2010 | PMID: 20359594 |
[The genotype-phenotype correlation of MYH7 gene G15391A mutation and MYBPC3 gene G12101A mutation in familial hypertrophic cardiomyopathy]. | WANG H | Zhonghua xin xue guan bing za zhi | 2008 | PMID: 19134269 |
Mutations profile in Chinese patients with hypertrophic cardiomyopathy. | Song L | Clinica chimica acta; international journal of clinical chemistry | 2005 | PMID: 15563892 |
Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. | Mörner S | Journal of molecular and cellular cardiology | 2003 | PMID: 12818575 |
The effects of vasoactive drugs on halothane inhibition of contractions of rat mesenteric lymphatics. | Takeshita T | Lymphology | 1989 | PMID: 2561168 |
Text-mined citations for rs727503191 ...
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.