ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2167C>G (p.Arg723Gly)
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.2167C>G (p.Arg723Gly)
Variation ID: 42885 Accession: VCV000042885.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23425814 (GRCh38) [ NCBI UCSC ] 14: 23895023 (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 9, 2015 Feb 14, 2024 Dec 15, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2167C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg723Gly missense NC_000014.9:g.23425814G>C NC_000014.8:g.23895023G>C NG_007884.1:g.14848C>G LRG_384:g.14848C>G LRG_384t1:c.2167C>G P12883:p.Arg723Gly - Protein change
- R723G
- Other names
- p.R723G:CGC>GGC
- NM_000257.3(MYH7):c.2167C>G
- Canonical SPDI
- NC_000014.9:23425813:G:C
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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 |
3419 | 4604 |
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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Pathogenic (1) |
criteria provided, single submitter
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Jun 28, 2016 | RCV000035771.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV000201494.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 18, 2020 | RCV000158837.9 | |
Pathogenic (3) |
reviewed by expert panel
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Dec 15, 2016 | RCV000227196.11 |
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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Pathogenic
(Dec 15, 2016)
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reviewed by expert panel
Method: curation
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV000564424.5
First in ClinVar: Jan 31, 2015 Last updated: Dec 11, 2022 |
Comment:
The c.2167C>G (p.Arg723Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PS4; PMID:11113006; PMID:19150014; PMID:17097032; Partners LMM ClinVar SCV000059422.5; SHaRe consortium, … (more)
The c.2167C>G (p.Arg723Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PS4; PMID:11113006; PMID:19150014; PMID:17097032; Partners LMM ClinVar SCV000059422.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:11113006). This variant was absent from large population studies (PM2; http://exac.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 disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>T p.Arg723Cys - ClinVar Variation ID 14095). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PP3 (less)
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Pathogenic
(Feb 02, 2017)
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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: SCV000208772.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 08, 2017 |
Comment:
The R723G pathogenic variant in the MYH7 gene has been reported in many individuals with HCM (Enjuto et al., 2000; Yang et al., 2006; Gacia-Castro … (more)
The R723G pathogenic variant in the MYH7 gene has been reported in many individuals with HCM (Enjuto et al., 2000; Yang et al., 2006; Gacia-Castro et al., 2009; Tripathi et al., 2011; Zheng et al., 2010; Coto et al., 2012; Marsiglia et al., 2013; Gomez et al., 2014). In multiple unrelated cases, the variant segregated with disease throughout large multi-generational families (Enjuto et al., 2000; Yang et al., 2010; Zheng et al., 2010). Allelic expression studies on skeletal and myocardium tissue from one family showed a larger R237G load compared to the wild-type allele, and load seemed to be correlated with disease severity (Enjuto et al., 2000; Tripathi et al., 2011). Additionally, the R723G variant has been reported as a likely pathogenic or pathogenic variant in multiple individuals with HCM who were referred for genetic testing at GeneDx and other clinical laboratories (ClinVar SCVSCV000256127.1, SCV000284260.1, SCV000059422.4; Landrum et al., 2016). Two variants at the same residue (R723C, R723H) are also reported as likely pathogenic or pathogenic.The R723G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R723G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, analysis of skeletal muscle and cardiomyocytes from individuals harboring the R723G variant showed myofibrillar deficiency and disarray with reduced calcium sensitivity and increased stiffness of the myosin-head, resulting in decreased force generation for cardiomyocytes, in particular (Seebohm et al., 2009; Kraft et al., 2013; Brenner et al., 2014). It is suggested that these effects activate stretch-sensitive signaling and, in turn, results in cardiac remodeling, the hallmark of HCM. (less)
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Pathogenic
(Oct 30, 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: SCV000928023.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(May 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059422.6
First in ClinVar: May 03, 2013 Last updated: Mar 04, 2019 |
Comment:
The p.Arg723Gly variant in MYH7 has been reported in the literature in at least four families with HCM, progressive CHF, and sudden cardiac death, segregated … (more)
The p.Arg723Gly variant in MYH7 has been reported in the literature in at least four families with HCM, progressive CHF, and sudden cardiac death, segregated wi th disease in >20 affected relatives, and was absent from 400 control chromosome s (Enjuto 2000, Yang 2006). This variant is also absent from large population st udies. This variant is reported in ClinVar (Variant ID 42885) and classified as pathogenic by an expert panel. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathog enic prediction is estimated to be correct 94% of the time (Jordan 2011). Of not e, this variant lies in the head region of the protein. Missense variants in thi s region have been reported and statistically indicated to be more likely to cau se disease (Walsh 2016). In summary, the p.Arg723Gly variant meets our criteria to be classified as pathogenic based upon segregation studies, absence in contro ls, and computational assessment. (less)
Number of individuals with the variant: 3
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Pathogenic
(Aug 18, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715069.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PP1_Strong, PS4, PS3, PM1, PM2, PM5, PP3
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe)
Accession: SCV000256127.1 First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015 |
Number of individuals with the variant: 4
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Pathogenic
(Jun 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747952.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Nov 27, 2023)
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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: SCV000284260.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 723 of the MYH7 protein (p.Arg723Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 723 of the MYH7 protein (p.Arg723Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 11113006, 17097032, 19150014, 20865685, 24093860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42885). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19651039, 23318932, 25346696). This variant disrupts the p.Arg723 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430197, 9829907, 12707239, 21835320). 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)
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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 genetic variants in adolescent patients with left ventricular noncompaction cardiomyopathy. | Liu S | International journal of cardiology | 2020 | PMID: 31918855 |
Hypertrophic cardiomyopathy MYH7 mutation R723G alters mRNA secondary structure. | Rose J | Physiological genomics | 2020 | PMID: 31790337 |
Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. | Norrish G | Circulation | 2019 | PMID: 31006259 |
Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. | Kelly MA | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29300372 |
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 |
Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development. | Brenner B | Frontiers in physiology | 2014 | PMID: 25346696 |
Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. | Marsiglia JD | American heart journal | 2013 | PMID: 24093860 |
Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. | Olivotto I | Journal of the American College of Cardiology | 2011 | PMID: 21835320 |
Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy. | Tripathi S | Basic research in cardiology | 2011 | PMID: 21769673 |
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. | Jordan DM | American journal of human genetics | 2011 | PMID: 21310275 |
The left and right ventricle of a patient with a R723G mutation of the beta-myosin heavy chain and severe hypertrophic cardiomyopathy show no differences in the expression of myosin mRNA. | Borchert B | Cardiology journal | 2010 | PMID: 20865685 |
Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance. | Seebohm B | Biophysical journal | 2009 | PMID: 19651039 |
[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. | García-Castro M | Revista espanola de cardiologia | 2009 | PMID: 19150014 |
Quantification of mutant versus wild-type myosin in human muscle biopsies using nano-LC/ESI-MS. | Becker E | Analytical chemistry | 2007 | PMID: 18020371 |
Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy. | Yang JH | Chinese medical journal | 2006 | PMID: 17097032 |
[Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene in a Chinese pedigree]. | Zheng DD | Zhonghua xin xue guan bing za zhi | 2006 | PMID: 16630450 |
Hypertrophic cardiomyopathy-related beta-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells. | Kirschner SE | American journal of physiology. Heart and circulatory physiology | 2005 | PMID: 15550524 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene. | Enjuto M | Journal of molecular and cellular cardiology | 2000 | PMID: 11113006 |
Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy. | Tesson F | Human mutation | 1998 | PMID: 9829907 |
Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. | Watkins H | The Journal of clinical investigation | 1992 | PMID: 1430197 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6c2b587c-45cc-4fbc-bc0b-059a87ea6349 | - | - | - | - |
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Text-mined citations for rs121913630 ...
HelpRecord last updated Feb 14, 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.