ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.6116G>A (p.Arg2039Gln)
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(10); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001130987.2(DYSF):c.6116G>A (p.Arg2039Gln)
Variation ID: 287816 Accession: VCV000287816.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.2 2: 71681053 (GRCh38) [ NCBI UCSC ] 2: 71908183 (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 Dec 6, 2016 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001130987.2:c.6116G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Arg2039Gln missense NM_003494.4:c.5999G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Arg2000Gln missense NM_001130455.2:c.6002G>A NP_001123927.1:p.Arg2001Gln missense NM_001130976.2:c.5957G>A NP_001124448.1:p.Arg1986Gln missense NM_001130977.2:c.6020G>A NP_001124449.1:p.Arg2007Gln missense NM_001130978.2:c.6062G>A NP_001124450.1:p.Arg2021Gln missense NM_001130979.2:c.6092G>A NP_001124451.1:p.Arg2031Gln missense NM_001130980.2:c.6050G>A NP_001124452.1:p.Arg2017Gln missense NM_001130981.2:c.6113G>A NP_001124453.1:p.Arg2038Gln missense NM_001130982.2:c.6095G>A NP_001124454.1:p.Arg2032Gln missense NM_001130983.2:c.6065G>A NP_001124455.1:p.Arg2022Gln missense NM_001130984.2:c.6023G>A NP_001124456.1:p.Arg2008Gln missense NM_001130985.2:c.6053G>A NP_001124457.1:p.Arg2018Gln missense NM_001130986.2:c.5960G>A NP_001124458.1:p.Arg1987Gln missense NC_000002.12:g.71681053G>A NC_000002.11:g.71908183G>A NG_008694.1:g.232431G>A LRG_845:g.232431G>A LRG_845t1:c.5999G>A LRG_845p1:p.Arg2000Gln LRG_845t2:c.6116G>A LRG_845p2:p.Arg2039Gln - Protein change
- R2039Q, R2000Q, R1986Q, R2001Q, R2032Q, R2018Q, R2022Q, R2038Q, R2008Q, R2021Q, R1987Q, R2007Q, R2017Q, R2031Q
- Other names
- p.Arg2000Gln
- Canonical SPDI
- NC_000002.12:71681052:G:A
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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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00019
Trans-Omics for Precision Medicine (TOPMed) 0.00028
The Genome Aggregation Database (gnomAD), exomes 0.00029
Exome Aggregation Consortium (ExAC) 0.00032
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
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
Help
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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DYSF | - | - |
GRCh38 GRCh37 |
4021 | 4070 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 23, 2022 | RCV000356385.8 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2022 | RCV000487973.26 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000675073.4 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001085395.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 18, 2021 | RCV001449928.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001138099.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 21, 2023 | RCV003448906.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jul 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800565.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely benign
(Apr 18, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000341726.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 4
Sex: mixed
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Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135891.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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DYSF-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001298125.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Miyoshi muscular dystrophy 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001653340.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Sex: mixed
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Uncertain significance
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Miyoshi muscular dystrophy 1
Affected status: no
Allele origin:
germline
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Pars Genome Lab
Accession: SCV001736804.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
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Uncertain significance
(Aug 29, 2019)
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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: SCV001802480.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17070050, 11468312, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17070050, 11468312, 27884173, 20981092, 20623375) (less)
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Uncertain significance
(Feb 23, 2022)
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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: SCV002103696.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: DYSF c.5999G>A (p.Arg2000Gln) results in a conservative amino acid change located in the Ferlin, C-terminal domain (IPR032362) of the encoded protein sequence. Four … (more)
Variant summary: DYSF c.5999G>A (p.Arg2000Gln) results in a conservative amino acid change located in the Ferlin, C-terminal domain (IPR032362) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251298 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00029 vs 0.0031), allowing no conclusion about variant significance. c.5999G>A has been reported in the literature in individuals affected with dysferlinopathy, including Limb-Girdle Muscular Dystrophy and Miyoshi myopathy (Aoki_2001, De Luna_2007, Bardakov_2021, Zhong_2021). Expression of the protein was determined to be absent or reduced in compound heterozygous and carrier individuals (De Luna_2007, De Luna_2012, Bardakov_2021). However, the variant has also been reported in the literature in multiple homozygous unaffected individuals (Boyden_2010, Abouelhoda_2016), while it was found to co-occur in cis with a pathogenic variant (DYSF c.5860G>T, p.Glu1954X) in a compound heterozygous patient. These reports do not provide unequivocal conclusions about association of the variant with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign and seven ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV004176293.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
Heterozygous variant NM_003494:c.5999G>A (p.Arg2000Gln) in the DYSF gene was found on WES data in female proband (50 y.o., Caucasian) with mitral valve prolapse, mitral insufficiency, … (more)
Heterozygous variant NM_003494:c.5999G>A (p.Arg2000Gln) in the DYSF gene was found on WES data in female proband (50 y.o., Caucasian) with mitral valve prolapse, mitral insufficiency, cardiomyopathy unspecified. An additional rare candidate variant NM_003737:c.2684C>T (p.Pro895Leu) in the DCHS1 gene (Class III of pathogenicity) was found in this proband. The NM_003494:c.5999G>A variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0002618 (Date of access 21-04-2023). This variant has been reported in 10 articles in patients with variable phenotypes (PMID: 35047756, 34559919, 33927379, 32906206, 27884173, 22910291, 22194990, 20623375, 17070050, 11468312). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2, PP3 (less)
Clinical Features:
Mitral valve prolapse (present) , Mitral regurgitation (present)
Age: 50-59 years
Sex: female
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Uncertain significance
(Nov 24, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003829582.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Qualitative or quantitative defects of dysferlin
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000649734.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Dec 01, 2019)
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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: SCV000575218.26
First in ClinVar: May 08, 2017 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Likely benign
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001457859.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Magnetic resonance imaging pattern variability in dysferlinopathy. | Bardakov SN | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2021 | PMID: 35047756 |
Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective. | Zhong H | Human mutation | 2021 | PMID: 34559919 |
Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients. | Charnay T | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33927379 |
Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India. | Narang A | Human mutation | 2020 | PMID: 32906206 |
Revisiting the morbid genome of Mendelian disorders. | Abouelhoda M | Genome biology | 2016 | PMID: 27884173 |
1α,25(OH)(2)-Vitamin D3 increases dysferlin expression in vitro and in a human clinical trial. | De Luna N | Molecular therapy : the journal of the American Society of Gene Therapy | 2012 | PMID: 22910291 |
Comparison of dysferlin expression in human skeletal muscle with that in monocytes for the diagnosis of dysferlin myopathy. | Gallardo E | PloS one | 2011 | PMID: 22194990 |
Efficient identification of novel mutations in patients with limb girdle muscular dystrophy. | Boyden SE | Neurogenetics | 2010 | PMID: 20623375 |
Dysferlin expression in monocytes: a source of mRNA for mutation analysis. | De Luna N | Neuromuscular disorders : NMD | 2007 | PMID: 17070050 |
Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. | Aoki M | Neurology | 2001 | PMID: 11468312 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF | - | - | - | - |
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Text-mined citations for rs115407852 ...
HelpRecord last updated Apr 15, 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.