ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2221G>A (p.Gly741Arg)
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.2221G>A (p.Gly741Arg)
Variation ID: 42890 Accession: VCV000042890.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23425760 (GRCh38) [ NCBI UCSC ] 14: 23894969 (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 Feb 28, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2221G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Gly741Arg missense NC_000014.9:g.23425760C>T NC_000014.8:g.23894969C>T NG_007884.1:g.14902G>A LRG_384:g.14902G>A LRG_384t1:c.2221G>A P12883:p.Gly741Arg - Protein change
- G741R
- Other names
- p.G741R:GGG>AGG
- Canonical SPDI
- NC_000014.9:23425759: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) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
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 |
3578 | 4827 |
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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Pathogenic (2) |
criteria provided, single submitter
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Nov 23, 2021 | RCV000158521.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2022 | RCV000243586.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000461730.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2022 | RCV001170500.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2022 | RCV003398598.4 |
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
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
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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
(Apr 22, 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: SCV000059429.6
First in ClinVar: May 03, 2013 Last updated: Oct 10, 2018 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 5
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Pathogenic
(Feb 18, 2022)
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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: SCV000320678.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.G741R pathogenic mutation (also known as c.2221G>A), located in coding exon 18 of the MYH7 gene, results from a G to A substitution at … (more)
The p.G741R pathogenic mutation (also known as c.2221G>A), located in coding exon 18 of the MYH7 gene, results from a G to A substitution at nucleotide position 2221. The glycine at codon 741 is replaced by arginine, an amino acid with dissimilar 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, and a different nucleotide substitution resulting in the same amino acid change (c.2221G>C), were reported to segregate with disease in families with hypertrophic cardiomyopathy (HCM) (Fananapazir L, Proc. Natl. Acad. Sci. U.S.A. 1993 May; 90(9):3993-7; Montag J et al. J. Muscle Res. Cell. Motil. 2017 Aug;38(3-4):291-302). The p.G741R alteration has been reported in multiple additional HCM cohorts (Richard P, Circulation 2003 May; 107(17):2227-32; Van Driest SL, J. Am. Coll. Cardiol. 2004 Aug; 44(3):602-10.; Song L, Clin. Chim. Acta 2005 Jan; 351(1-2):209-16; Kindel SJ, J. Card. Fail. 2012 May; 18(5):396-403; Marsiglia JD, Am. Heart J. 2013 Oct; 166(4):775-82; Berge KE, Clin. Genet. 2014 Oct; 86(4):355-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, another alteration involving the same amino acid (p.G741W, c.2221G>T) has also been reported in association with HCM (Arai S et al. Am J Med Genet. 1995;58:267-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 23, 2021)
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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: SCV000208456.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in several other individuals with HCM; however, the nucleotide change was not specified (Malinchik et al., 1997; Van Driest et al., 2004; Kaski et … (more)
Reported in several other individuals with HCM; however, the nucleotide change was not specified (Malinchik et al., 1997; Van Driest et al., 2004; Kaski et al., 2009; Theis et al., 2009; Kindel et al., 2012; Marsiglia et al., 2013; Miller et al., 2013; Berge et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#42890; ClinVar); This variant is associated with the following publications: (PMID: 15358028, 7731997, 22555271, 21216834, 9742053, 20031618, 19808356, 12707239, 25935763, 24093860, 9140824, 8483915, 15563892, 26743238, 28246639, 27247418, 27532257, 29101517, 24111713, 29343710, 23054336, 24704860) (less)
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Pathogenic
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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MYH7-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119604.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MYH7 c.2221G>A variant is predicted to result in the amino acid substitution p.Gly741Arg. This variant was reported in numerous individuals with hypertrophic cardiomyopathy (Fananapazir … (more)
The MYH7 c.2221G>A variant is predicted to result in the amino acid substitution p.Gly741Arg. This variant was reported in numerous individuals with hypertrophic cardiomyopathy (Fananapazir et al. 1993. PubMed ID: 8483915; Table S1, Captur et al. 2014. PubMed ID: 24704860; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Filatova et al. 2021. PubMed ID: 34598319). Functional studies in patient-derived muscle fibers showed that the p.Gly741Arg substitution could alter the contractile properties of the mutant protein (Lankford and Fananapazir. 1995. PubMed ID: 7883988). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23894969-C-T). Other different nucleotide substitutions affecting the same amino acid (p.Gly741Trp and p.Gly741Ala) have been reported in individuals with hypertrophic cardiomyopathy (Arai et al. 1995. PubMed ID: 8533830; Van Driest et al. 2004. PubMed ID: 15358028). The c.2221G>A (p.Gly741Arg) variant is interpreted as pathogenic. (less)
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Pathogenic
(Apr 07, 2022)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333083.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
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Pathogenic
(Jan 22, 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: SCV000546276.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 741 of the MYH7 protein (p.Gly741Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 741 of the MYH7 protein (p.Gly741Arg). This variant is present in population databases (rs121913632, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8483915, 12707239, 20800588, 24111713, 25935763). ClinVar contains an entry for this variant (Variation ID: 42890). 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.Gly741 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8533830, 15856146, 22112859, 26914223). 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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Pathogenic
(Jul 15, 2014)
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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: SCV000280318.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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.Gly741Arg in the MYH7 gene. This variant has been seen in at least 9 cases of HCM. Fananapazir (1993) reported the variant in two unrelated families with HCM; the variant co-segregated with HCM in three affected members of one family and two affected members of the other family. Song et al (2005) observed the variant arising de novo in an individual with HCM. Richard et al (2003) reported the variant in one individual with HCM. Millat et al (2010) reported the identification of this variant in a cohort of individuals studied using high resolution melting to identify variants (this case may be redundant with the Richards et al case as both came from French cohorts). Keller et al (2005) reported the variant in a woman with HCM in their Swiss cohort. Kaski et al (2009) observed the variant in two unrelated children with HCM in a British cohort. We have also observed this variant in another patient with HCM in our clinic. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this to be disease causing. The glycine at codon 741 is conserved across species, as are neighboring amino acids. Two other variants at the same codon have been associated with cardiomyopathy: p.Gly741Ala (primary data unavailable), p.Gly741Trp (we consider this variant likely disease causing). Variants at nearby codons have also been reported in association with cardiomyopathy (p.Ile736Val, p.Ile736Thr, p.Ile736Met, p.Ala742Glu, p.Glu743Asp). Functional studies have shown that p.Gly741Arg confers reduced isometric force generation and decreased velocity of shortening (Lankford et al 1995). In total the variant has not been seen in ~6,720 published controls and publicly available population datasets. There is no variation at codon 741 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). There is also no variation at codon 741 listed in dbSNP or 1000 genomes (as of 9/20/13). The variant was not observed in the following published control samples: 120 general population individuals studied by Song et al (2005) (likely Chinese ancestry), 100 healthy adults reported by Richard et al (2003). No further control data was provided by GeneDx or the other authors cited above. (less)
Number of individuals with the variant: 10
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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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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 |
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 |
Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain. | García-Giustiniani D | Heart (British Cardiac Society) | 2015 | PMID: 25935763 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. | Marsiglia JD | American heart journal | 2013 | PMID: 24093860 |
Pediatric cardiomyopathy: importance of genetic and metabolic evaluation. | Kindel SJ | Journal of cardiac failure | 2012 | PMID: 22555271 |
Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. | Otsuka H | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22112859 |
Development of a high resolution melting method for the detection of genetic variations in hypertrophic cardiomyopathy. | Millat G | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20800588 |
Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. | Kaski JP | Circulation. Cardiovascular genetics | 2009 | PMID: 20031618 |
Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. | Perrot A | Journal of molecular medicine (Berlin, Germany) | 2005 | PMID: 15856146 |
Mutations profile in Chinese patients with hypertrophic cardiomyopathy. | Song L | Clinica chimica acta; international journal of clinical chemistry | 2005 | PMID: 15563892 |
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15358028 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Isometric tension and mutant myosin heavy chain content in single skeletal myofibers from hypertrophic cardiomyopathy patients. | Malinchik S | Journal of molecular and cellular cardiology | 1997 | PMID: 9140824 |
Missense mutation of the beta-cardiac myosin heavy-chain gene in hypertrophic cardiomyopathy. | Arai S | American journal of medical genetics | 1995 | PMID: 8533830 |
Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. | Rayment I | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7731997 |
Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. | Fananapazir L | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8483915 |
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Text-mined citations for rs121913632 ...
HelpRecord last updated Mar 11, 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.