ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3815-1G>A
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(8); Uncertain significance(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.3815-1G>A
Variation ID: 42746 Accession: VCV000042746.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47331882 (GRCh38) [ NCBI UCSC ] 11: 47353433 (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 Apr 20, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3815-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000011.10:g.47331882C>T NC_000011.9:g.47353433C>T NG_007667.1:g.25821G>A NG_029462.1:g.67507C>T NG_029462.2:g.67696C>T LRG_386:g.25821G>A LRG_386t1:c.3815-1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:47331881: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3890 | 3907 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 20, 2018 | RCV000158273.3 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 23, 2016 | RCV000208066.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2021 | RCV000618617.3 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2023 | RCV000701771.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 26, 2020 | RCV001264482.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2023 | RCV003531914.1 |
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
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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
(Dec 01, 2021)
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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: SCV000739990.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.3815-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the MYBPC3 gene. Alterations that disrupt … (more)
The c.3815-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This alteration occurs at the 3' terminus of the MYBPC3 gene, is not expected to trigger nonsense-mediated mRNAdecay, and results in a frameshift that is predicted to impact only the last 3 amino acids of the native protein, although it is also expected to elongate the translated protein. The exact functional effect of this alteration is unknown. This variant has been identified in patients with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 13, 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: SCV000830587.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 33 of the MYBPC3 gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects an acceptor splice site in intron 33 of the MYBPC3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs397516044, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 42746). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. (less)
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Likely pathogenic
(Dec 07, 2015)
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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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Blueprint Genetics
Accession: SCV000264063.2
First in ClinVar: Feb 27, 2016 Last updated: May 29, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 23, 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: SCV000747923.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Likely pathogenic
(Mar 20, 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: SCV000208208.11
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
The c.3815-1 G>A likely pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Alfares et al., 2015; Walsh et al., … (more)
The c.3815-1 G>A likely pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Alfares et al., 2015; Walsh et al., 2017). This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The c.3815-1 G>A variant destroys the canonical splice acceptor site in intron 33 and is predicted to cause skipping of exon 34, the last coding exon of the MYBPC3 gene. Skipping of exon 34 would result in the loss of 3 amino acid residues and the natural termination codon, ultimately leading to extension of the protein length by using non-coding exon 35. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Other splice site variants in the MYBPC3 gene, and one downstream nonsense variant, have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, the c.3815-1 G>A variant is not observed at significant frequency in large population cohorts (Lek et al., 2016). (less)
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Likely pathogenic
(Sep 30, 2011)
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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: SCV000059272.5
First in ClinVar: May 03, 2013 Last updated: Aug 14, 2019 |
Comment:
The 3815-1G>A variant has not been previously reported or been identified by our laboratory. This variant is predicted to cause abnormal splicing because the nu … (more)
The 3815-1G>A variant has not been previously reported or been identified by our laboratory. This variant is predicted to cause abnormal splicing because the nu cleotide substitution occurs in the highly conserved splice consensus sequence. Pathogenic splice variants in MYBPC3 are common in patients with HCM, which sup ports a disease causing role. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 26, 2020)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442656.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Variant summary: MYBPC3 c.3815-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: MYBPC3 c.3815-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The potentially skipped exon (exon 34) only encodes the last 3 amino acids of the protein. Thus the consequence of skipping of exon 34 is not clear. The variant allele was found at a frequency of 4.1e-06 in 242650 control chromosomes. c.3815-1G>A has been reported in the literature in at least one individual affected with HCM (Alfares_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five laboratories classified this variant as pathogenic/likely pathogenic, however, the most recent submission classified this variant as VUS. Based on the evidence outlined above, the variant was classified as VUS. (less)
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Likely pathogenic
(Jun 01, 2023)
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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: SCV004358617.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict … (more)
This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004826934.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict … (more)
This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809457.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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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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Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
False-Positive (99m)Technetium-Pyrophosphate Scintigraphy in Two Patients With Hypertrophic Cardiomyopathy. | Schafer EB | Circulation. Heart failure | 2021 | PMID: 33663232 |
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 |
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 |
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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
[Nonribosomal ribonucleoprotein particles in preparations of nonhistone proteins extracted from pigeon erythroblast chromatin]. | Stvolinskaia NS | Molekuliarnaia biologiia | 1978 | PMID: 739990 |
[Herpes panaritium]. | Gammeltoft M | Ugeskrift for laeger | 1978 | PMID: 208208 |
Text-mined citations for rs397516044 ...
HelpRecord last updated May 08, 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.