ClinVar Genomic variation as it relates to human health
NM_032578.4(MYPN):c.3481C>A (p.Leu1161Ile)
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.
Uncertain significance(2); Benign(8); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_032578.4(MYPN):c.3481C>A (p.Leu1161Ile)
Variation ID: 31819 Accession: VCV000031819.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.3 10: 68199563 (GRCh38) [ NCBI UCSC ] 10: 69959320 (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 Apr 4, 2013 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032578.4:c.3481C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_115967.2:p.Leu1161Ile missense NM_001256267.2:c.3481C>A NP_001243196.1:p.Leu1161Ile missense NM_001256268.2:c.2599C>A NP_001243197.1:p.Leu867Ile missense NR_045662.4:n.3018C>A non-coding transcript variant NR_045663.4:n.3555C>A non-coding transcript variant NC_000010.11:g.68199563C>A NC_000010.10:g.69959320C>A NG_032118.1:g.98447C>A LRG_410:g.98447C>A LRG_410t1:c.3481C>A LRG_410p1:p.Leu1161Ile Q86TC9:p.Leu1161Ile - Protein change
- L1161I, L867I
- Other names
- p.L1161I:CTC>ATC
- Canonical SPDI
- NC_000010.11:68199562:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- probably has functional consequence
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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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0.00220 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00234
Trans-Omics for Precision Medicine (TOPMed) 0.00254
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00123
1000 Genomes Project 0.00220
Exome Aggregation Consortium (ExAC) 0.00330
The Genome Aggregation Database (gnomAD), exomes 0.00381
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MYPN | - | - |
GRCh38 GRCh37 |
1558 | 1607 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV000024512.26 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jul 29, 2023 | RCV000216191.20 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 24, 2019 | RCV000852614.9 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000206974.27 | |
Benign (1) |
criteria provided, single submitter
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Apr 25, 2016 | RCV000247848.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 28, 2017 | RCV000624690.11 |
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
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 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Dilated cardiomyopathy Heart failure
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995317.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 3
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Benign
(Aug 11, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159431.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
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Benign
(Feb 03, 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: SCV000236066.6
First in ClinVar: Jul 05, 2015 Last updated: Mar 08, 2017 |
Comment:
Identified in a patient with HCM in the published literature (Purevjav et al., 2012); In silico analysis supports that this missense variant does not alter … (more)
Identified in a patient with HCM in the published literature (Purevjav et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 22286171, 27535533) (less)
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Likely benign
(Jul 29, 2023)
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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: SCV004029750.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
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Benign
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004042487.5
First in ClinVar: Oct 14, 2023 Last updated: Apr 15, 2024 |
Comment:
MYPN: BS1, BS2
Number of individuals with the variant: 1
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Benign
(Apr 25, 2016)
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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: SCV000318077.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Dilated cardiomyopathy 1KK
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267413.1
First in ClinVar: May 24, 2017 Last updated: May 24, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely Benign
(Feb 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511278.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Likely benign.
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Uncertain significance
(Mar 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Primary familial dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740629.1
First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018 |
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Likely benign
(Jul 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1KK
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743691.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Benign
(May 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1KK
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745068.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Benign
(Jun 03, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000269405.3
First in ClinVar: May 29, 2016 Last updated: Nov 08, 2018 |
Comment:
p.Leu1161Ile in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 2.8% (320/11566) of … (more)
p.Leu1161Ile in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 2.8% (320/11566) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138313730). (less)
Number of individuals with the variant: 2
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Benign
(-)
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criteria provided, single submitter
Method: research
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Dilated cardiomyopathy 1KK
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435224.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The heterozygous p.Leu1161Ile variant in MYPN has been identified in an American Indian Alaskan individual with hypertrophic cardiomyopathy (PMID: 22286171). This variant has also been … (more)
The heterozygous p.Leu1161Ile variant in MYPN has been identified in an American Indian Alaskan individual with hypertrophic cardiomyopathy (PMID: 22286171). This variant has also been identified in >2% of Latino chromosomes and 5 homozygotes by ExAC (http://gnomad.broadinstitute.org/), and in 3 individuals from the NHLBI GO Exome Sequencing Project (PMID: 23299917). In summary, this variant meets criteria to be classified as benign for hypertrophic cardiomyopathy. (less)
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1KK
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000291122.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Uncertain significance
(Jun 27, 2013)
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no assertion criteria provided
Method: literature only
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Dilated cardiomyopathy 1KK
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000244008.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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Benign
(Oct 13, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280393.2
First in ClinVar: Jun 01, 2016 Last updated: Nov 08, 2018 |
Comment:
p.Leu1161Ile (c.3481 C>A) in the MYPN gene Given the weak disease-gene association, the weak case data, and the presence in ancestry-matched general population samples, we … (more)
p.Leu1161Ile (c.3481 C>A) in the MYPN gene Given the weak disease-gene association, the weak case data, and the presence in ancestry-matched general population samples, we consider this variant a variant of uncertain significance. MYPN (NM_032578.2) encodes myopalladin, a protein component of the sarcomere. Heterozygous mutations in MYPN have been reported in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) (Purevjav et al. 2012 Hum Molec Genet 21(9):2039-2053; Meyer et al. 2012 Eur J Hum Genet Epub ahead of print). However, when Megan Grove from our team reviewed the supporting data in 2012 we felt that it was weak. The variant has been seen in at least 1 unrelated case of hypertrophic cardiomyopathy (not including this patient's family). There is no segregation data available. Purevjav et al (2012) observed the variant in an American Indian/Alaskan male with HCM who had undergone myectomy. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The variant occurs in the alpha-actinin binding domain. This is a conservative amino acid change from nonpolar leucine to a nonpolar isoleucine at a residue that is highly conserved across vertebrate species (it is a nonpolar phenylalanine in squirrel). It is predicted to be "probably damaging" and "tolerated" by PolyPhen and SIFT in silico analyses, respectively. [UPDATED in 2016] In total the variant has not been seen in at least 400 of >60,000 published controls and individuals from publicly available population datasets. It is present in 400 individuals in ExAC, across multiple ethnicities. The variant was reported in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of September 12th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per GeneDx, the variant was observed in the 1000 Genomes samples: 3/551 (0.5%) alleles from individuals of Asian background and in 1/349 (0.3%) alleles of individuals of Hispanic ancestry. The variant was not observed in the following published control samples: 1020 (Purejeav et al 2012). (less)
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919358.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958066.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(Apr 27, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (MYPN)
Accession: SCV000045816.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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probably has functional consequence
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Leiden Muscular Dystrophy (MYPN)
Accession: SCV000045816.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. | Purevjav E | Human molecular genetics | 2012 | PMID: 22286171 |
http://web.expasy.org/variant_pages/VAR_069660.html | - | - | - | - |
Text-mined citations for rs138313730 ...
HelpRecord last updated May 01, 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.