ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.2956A>T (p.Met986Leu)
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(8); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001130987.2(DYSF):c.2956A>T (p.Met986Leu)
Variation ID: 196022 Accession: VCV000196022.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.2 2: 71569911 (GRCh38) [ NCBI UCSC ] 2: 71797041 (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.2956A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Met986Leu missense NM_003494.4:c.2902A>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Met968Leu missense NM_001130455.2:c.2905A>T NP_001123927.1:p.Met969Leu missense NM_001130976.2:c.2860A>T NP_001124448.1:p.Met954Leu missense NM_001130977.2:c.2860A>T NP_001124449.1:p.Met954Leu missense NM_001130978.2:c.2902A>T NP_001124450.1:p.Met968Leu missense NM_001130979.2:c.2995A>T NP_001124451.1:p.Met999Leu missense NM_001130980.2:c.2953A>T NP_001124452.1:p.Met985Leu missense NM_001130981.2:c.2953A>T NP_001124453.1:p.Met985Leu missense NM_001130982.2:c.2998A>T NP_001124454.1:p.Met1000Leu missense NM_001130983.2:c.2905A>T NP_001124455.1:p.Met969Leu missense NM_001130984.2:c.2863A>T NP_001124456.1:p.Met955Leu missense NM_001130985.2:c.2956A>T NP_001124457.1:p.Met986Leu missense NM_001130986.2:c.2863A>T NP_001124458.1:p.Met955Leu missense NC_000002.12:g.71569911A>T NC_000002.11:g.71797041A>T NG_008694.1:g.121289A>T LRG_845:g.121289A>T LRG_845t1:c.2902A>T LRG_845p1:p.Met968Leu LRG_845t2:c.2956A>T LRG_845p2:p.Met986Leu - Protein change
- M968L, M986L, M1000L, M954L, M955L, M985L, M969L, M999L
- Other names
- -
- Canonical SPDI
- NC_000002.12:71569910:A: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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00040
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00185
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD) 0.00112
Trans-Omics for Precision Medicine (TOPMed) 0.00123
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 |
4008 | 4057 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000367959.13 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000403556.13 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Apr 1, 2023 | RCV000725533.35 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV001079396.21 | |
not provided (1) |
no classification provided
|
- | RCV001535633.8 | |
Benign (1) |
no assertion criteria provided
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Jan 12, 2020 | RCV001272822.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 18, 2021 | RCV001449649.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 20, 2021 | RCV001810433.11 |
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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Uncertain significance
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi Muscular Dystrophy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000431775.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
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Uncertain significance
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Limb-Girdle Muscular Dystrophy, Recessive
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000431776.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Nov 19, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000337583.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 9
Sex: mixed
|
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Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Qualitative or quantitative defects of dysferlin
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001297771.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(May 18, 2021)
|
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: SCV001652848.1
First in ClinVar: May 28, 2021 Last updated: May 28, 2021 |
Sex: mixed
|
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Uncertain significance
(Oct 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2B
Miyoshi muscular dystrophy 1 Distal myopathy with anterior tibial onset
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060089.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_003494.3(DYSF):c.2902A>T(M968L) is a missense variant classified as a variant of uncertain significance in the context of dysferlinopathy. M968L has been observed in cases with relevant … (more)
NM_003494.3(DYSF):c.2902A>T(M968L) is a missense variant classified as a variant of uncertain significance in the context of dysferlinopathy. M968L has been observed in cases with relevant disease (PMID: 18832576, 30564623, 24239059). Functional assessments of this variant are not available in the literature. M968L has been observed in population frequency databases (gnomAD: NFE 0.22%). In summary, there is insufficient evidence to classify NM_003494.3(DYSF):c.2902A>T(M968L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
|
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Uncertain significance
(Jul 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV000613196.4
First in ClinVar: Apr 03, 2017 Last updated: Dec 31, 2022 |
|
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Likely benign
(May 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000583084.5
First in ClinVar: Apr 03, 2017 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 24239059, 30564623, 18832576, 24438169)
|
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Uncertain significance
(Mar 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224924.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 1
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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: SCV000649644.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 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: SCV001746364.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Comment:
DYSF: BS2
Number of individuals with the variant: 4
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979996.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Benign
(Jan 12, 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: SCV001455212.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002075177.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
Variant interpreted as Likely benign and reported on 05-29-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely benign and reported on 05-29-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormal muscle physiology (present) … (more)
Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-05-29
Testing laboratory interpretation: Likely benign
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not provided
(-)
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no classification provided
Method: phenotyping only
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DYSF-Related Disorders
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749661.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Clinical Features:
Abnormality of the chin (present) , Orofacial cleft (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormal … (more)
Abnormality of the chin (present) , Orofacial cleft (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormal delivery (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-05-29
Testing laboratory interpretation: Likely benign
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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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Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
Crystal structures of the human Dysferlin inner DysF domain. | Sula A | BMC structural biology | 2014 | PMID: 24438169 |
Anoctamin 5 muscular dystrophy associated with a silent p.Leu115Leu mutation resulting in exon skipping. | Joshi PR | Neuromuscular disorders : NMD | 2014 | PMID: 24239059 |
Dysferlin deficiency shows compensatory induction of Rab27A/Slp2a that may contribute to inflammatory onset. | Kesari A | The American journal of pathology | 2008 | PMID: 18832576 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF | - | - | - | - |
https://reader.elsevier.com/reader/sd/pii/S2667049622000266?token=14383976D1868D903F7DBCB252FBC9CFD331EBB2B7DEA6CA7C8BAC2FF9B9411322FEA09A4301862BB13D1A4EF0776125&originRegion=us-east-1&originCreation=20230308171527 | - | - | - | - |
Variant classified as Likely Benign and reported on 05/29/2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. | - | - | - | - |
Text-mined citations for rs144636654 ...
HelpRecord last updated Apr 20, 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.