ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.1609G>A (p.Gly537Arg)
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_001130987.2(DYSF):c.1609G>A (p.Gly537Arg)
Variation ID: 6679 Accession: VCV000006679.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.2 2: 71551073 (GRCh38) [ NCBI UCSC ] 2: 71778203 (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 Feb 14, 2024 Mar 26, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001130987.2:c.1609G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Gly537Arg missense NM_003494.4:c.1555G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Gly519Arg missense NM_001130455.2:c.1558G>A NP_001123927.1:p.Gly520Arg missense NM_001130976.2:c.1513G>A NP_001124448.1:p.Gly505Arg missense NM_001130977.2:c.1513G>A NP_001124449.1:p.Gly505Arg missense NM_001130978.2:c.1555G>A NP_001124450.1:p.Gly519Arg missense NM_001130979.2:c.1648G>A NP_001124451.1:p.Gly550Arg missense NM_001130980.2:c.1606G>A NP_001124452.1:p.Gly536Arg missense NM_001130981.2:c.1606G>A NP_001124453.1:p.Gly536Arg missense NM_001130982.2:c.1651G>A NP_001124454.1:p.Gly551Arg missense NM_001130983.2:c.1558G>A NP_001124455.1:p.Gly520Arg missense NM_001130984.2:c.1516G>A NP_001124456.1:p.Gly506Arg missense NM_001130985.2:c.1609G>A NP_001124457.1:p.Gly537Arg missense NM_001130986.2:c.1516G>A NP_001124458.1:p.Gly506Arg missense NC_000002.12:g.71551073G>A NC_000002.11:g.71778203G>A NG_008694.1:g.102451G>A LRG_845:g.102451G>A LRG_845t1:c.1555G>A LRG_845p1:p.Gly519Arg LRG_845t2:c.1609G>A LRG_845p2:p.Gly537Arg O75923:p.Gly519Arg - Protein change
- G519R, G537R, G520R, G506R, G536R, G550R, G505R, G551R
- Other names
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- Canonical SPDI
- NC_000002.12:71551072: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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
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 |
4062 | 4111 |
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
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 (1) |
no assertion criteria provided
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Apr 17, 2007 | RCV000007066.5 | |
Pathogenic (3) |
criteria provided, single submitter
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Sep 26, 2016 | RCV000342783.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2019 | RCV001048974.8 |
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
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 26, 2016)
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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: SCV000329868.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Comment:
The c.1555 G>A pathogenic variant in the DYSF gene has been previously reported in the homozygous state in two siblings with Miyoshi myopathy and absent … (more)
The c.1555 G>A pathogenic variant in the DYSF gene has been previously reported in the homozygous state in two siblings with Miyoshi myopathy and absent dysferlin expression on Western blot. Additionally, it was observed in the heterozygous state in their father with calf myalgias and progressive difficulty with walking (Illa et al., 2007). Functional studies demonstrate the c.1555 G>A variant creates a new splice acceptor site resulting in an out-of-frame deletion of 35 base pairs in exon 18 (De Luna et al., 2007; Kergourlay et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
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Likely pathogenic
(Mar 26, 2019)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001213004.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 25312915). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be homozygous or in combination with another DYSF variant in individuals affected with distal myopathy (PMID: 17287450, 30107846). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6679). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 519 of the DYSF protein (p.Gly519Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. (less)
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Pathogenic
(Apr 17, 2007)
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no assertion criteria provided
Method: literature only
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MIYOSHI MUSCULAR DYSTROPHY 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027262.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
In 2 sibs with Miyoshi myopathy (MMD1; 254130), Illa et al. (2007) identified a homozygous 1555G-A transition in exon 18 of the DYSF gene, resulting … (more)
In 2 sibs with Miyoshi myopathy (MMD1; 254130), Illa et al. (2007) identified a homozygous 1555G-A transition in exon 18 of the DYSF gene, resulting in a gly519-to-arg (G519R) substitution. Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. (less)
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Pathogenic
(Jul 01, 2019)
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no assertion criteria provided
Method: reference population
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not provided
Affected status: yes
Allele origin:
paternal
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Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Accession: SCV001244909.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
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Uncertain significance
(Jul 02, 2015)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000332008.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Identification of splicing defects caused by mutations in the dysferlin gene. | Kergourlay V | Human mutation | 2014 | PMID: 25312915 |
Symptomatic dysferlin gene mutation carriers: characterization of two cases. | Illa I | Neurology | 2007 | PMID: 17287450 |
Dysferlin expression in monocytes: a source of mRNA for mutation analysis. | De Luna N | Neuromuscular disorders : NMD | 2007 | PMID: 17070050 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF | - | - | - | - |
Text-mined citations for rs121908962 ...
HelpRecord last updated Sep 29, 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.