The c.2779delG pathogenic variant in the DYSF gene has been previously reported multiple times in association with DYSF-related disorders when present in the homozygous state or when in trans with another pathogenic DYSF variant (Krahn et al., 2009; Paradas et al., 2009; Ceyhan-Birsoy et al., 2015). This variant is observed in 7/34,416 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). The c.2779delG variant causes a frameshift starting with codon Alanine 927, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Ala927LeufsX21. This variant is predicted to cause loss of normal protein function either through protein truncation of nonsense-mediated mRNA decay.
ClinVar Genomic variation as it relates to human health
NM_003494.3(DYSF):c.2779del (p.Ala927Leufs)
Germline
Classification
Help
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.
(12)
Help
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.
Pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003494.3(DYSF):c.2779del (p.Ala927Leufs)
Variation ID: 6685 Accession: VCV000006685.44
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 2p13.2 2: 71568305 (GRCh38) [ NCBI UCSC ] 2: 71795435 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Feb 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130987.2:c.2833del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Ala945fs frameshift NM_003494.4:c.2779del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Ala927fs frameshift NM_003494.4:c.2779delG MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001130455.2:c.2782del NP_001123927.1:p.Ala928fs frameshift NM_001130976.2:c.2737del NP_001124448.1:p.Ala913fs frameshift NM_001130977.2:c.2737del NP_001124449.1:p.Ala913fs frameshift NM_001130978.2:c.2779del NP_001124450.1:p.Ala927fs frameshift NM_001130979.2:c.2872del NP_001124451.1:p.Ala958fs frameshift NM_001130980.2:c.2830del NP_001124452.1:p.Ala944fs frameshift NM_001130981.2:c.2830del NP_001124453.1:p.Ala944fs frameshift NM_001130982.2:c.2875del NP_001124454.1:p.Ala959fs frameshift NM_001130983.2:c.2782del NP_001124455.1:p.Ala928fs frameshift NM_001130984.2:c.2740del NP_001124456.1:p.Ala914fs frameshift NM_001130985.2:c.2833del NP_001124457.1:p.Ala945fs frameshift NM_001130986.2:c.2740del NP_001124458.1:p.Ala914fs frameshift NM_003494.3:c.2779delG NC_000002.12:g.71568307del NC_000002.11:g.71795437del NG_008694.1:g.119685del LRG_845:g.119685del LRG_845t1:c.2779del LRG_845p1:p.Ala927fs LRG_845t2:c.2833del LRG_845p2:p.Ala945fs - Protein change
- A914fs, A928fs, A944fs, A959fs, A913fs, A927fs, A945fs, A958fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:71568304:GGG:GG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
- Comment on variant
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| DYSF | - | - |
GRCh38 GRCh37 |
4065 | 4114 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
no assertion criteria provided
|
Sep 16, 2020 | RCV000007072.11 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 19, 2023 | RCV000599552.27 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 24, 2023 | RCV000546602.13 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 24, 2024 | RCV000311139.13 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000709975.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
The c.2779delG pathogenic variant in the DYSF gene has been previously reported multiple times in association with DYSF-related disorders when present in the homozygous state … (more)
The c.2779delG pathogenic variant in the DYSF gene has been previously reported multiple times in association with DYSF-related disorders when present in the homozygous state or when in trans with another pathogenic DYSF variant (Krahn et al., 2009; Paradas et al., 2009; Ceyhan-Birsoy et al., 2015). This variant is observed in 7/34,416 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). The c.2779delG variant causes a frameshift starting with codon Alanine 927, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Ala927LeufsX21. This variant is predicted to cause loss of normal protein function either through protein truncation of nonsense-mediated mRNA decay. (less)
|
|
|
Pathogenic
(Nov 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228343.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 17
Sex: mixed
|
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764676.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Elevated circulating creatine kinase concentration (present) , Myopathy (present)
|
|
|
Pathogenic
(Jun 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021826.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003916115.13
First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024 |
Comment:
DYSF: PVS1, PM2, PM3, PS4:Supporting
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001477220.3
First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID:25821721, 22194990, 19084402, 16010686, 18853459, 17825554). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
|
|
|
Pathogenic
(Dec 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Qualitative or quantitative defects of dysferlin
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000649638.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala927Leufs*21) in the DYSF gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ala927Leufs*21) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs745407251, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy or pseudometabolic muscular dystrophy (PMID: 16010686, 17825554, 18832576, 18853459, 19084402, 22194990, 25821721). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6685). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194187.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Dec 18, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Miyoshi muscular dystrophy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Diseases Diagnostic Center, Koc University Hospital
Accession: SCV000864397.1
First in ClinVar: Jul 01, 2019 Last updated: Jul 01, 2019 |
|
|
|
Pathogenic
(Jan 01, 2009)
|
no assertion criteria provided
Method: literature only
|
MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027268.6
First in ClinVar: Apr 04, 2013 Last updated: Jul 31, 2019 |
Comment on evidence:
In 2 Spanish sibs, aged 2 and 5 years, with unusual congenital onset of limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Paradas et al. (2009) … (more)
In 2 Spanish sibs, aged 2 and 5 years, with unusual congenital onset of limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Paradas et al. (2009) identified a homozygous 1-bp deletion (2776delG) in exon 26 of the DYSF gene, resulting in a frameshift and premature termination. The parents were not consanguineous, but they came from the same small village, and haplotype analysis suggested an ancient consanguineous relationship. Both patients presented in infancy with hypotonia and delayed motor development. They had difficulty walking, running, and climbing stairs, as well as neck muscle weakness. The patients had almost no expression of dysferlin in muscle, whereas clinically unaffected family members who were heterozygous for the mutation had about a 50% reduction in dysferlin expression. Paradas et al. (2009) emphasized the early onset of this disorder in these sibs, and suggested that they have a novel phenotype not previously associated with DYSF mutations. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458660.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Miyoshi muscular dystrophy 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001981612.2
First in ClinVar: Oct 25, 2021 Last updated: Oct 01, 2022 |
Comment:
Founder variant in Jews of the Caucasus
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
DYSF: PVS1, PM2, PM3, PS4:Supporting
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID:25821721, 22194990, 19084402, 16010686, 18853459, 17825554). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Ala927Leufs*21) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs745407251, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy or pseudometabolic muscular dystrophy (PMID: 16010686, 17825554, 18832576, 18853459, 19084402, 22194990, 25821721). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6685). For these reasons, this variant has been classified as Pathogenic.
Comment:
Founder variant in Jews of the Caucasus
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. |
Comment:
The c.2779delG pathogenic variant in the DYSF gene has been previously reported multiple times in association with DYSF-related disorders when present in the homozygous state or when in trans with another pathogenic DYSF variant (Krahn et al., 2009; Paradas et al., 2009; Ceyhan-Birsoy et al., 2015). This variant is observed in 7/34,416 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). The c.2779delG variant causes a frameshift starting with codon Alanine 927, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Ala927LeufsX21. This variant is predicted to cause loss of normal protein function either through protein truncation of nonsense-mediated mRNA decay.
Comment:
DYSF: PVS1, PM2, PM3, PS4:Supporting
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID:25821721, 22194990, 19084402, 16010686, 18853459, 17825554). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Ala927Leufs*21) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs745407251, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy or pseudometabolic muscular dystrophy (PMID: 16010686, 17825554, 18832576, 18853459, 19084402, 22194990, 25821721). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6685). For these reasons, this variant has been classified as Pathogenic.
Comment:
Founder variant in Jews of the Caucasus
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Dysferlinopathy. | Adam MP | - | 2021 | PMID: 20301480 |
| Whole Exome Sequencing Reveals DYSF, FKTN, and ISPD Mutations in Congenital Muscular Dystrophy Without Brain or Eye Involvement. | Ceyhan-Birsoy O | Journal of neuromuscular diseases | 2015 | PMID: 25821721 |
| 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 |
| A new phenotype of dysferlinopathy with congenital onset. | Paradas C | Neuromuscular disorders : NMD | 2009 | PMID: 19084402 |
| Analysis of the DYSF mutational spectrum in a large cohort of patients. | Krahn M | Human mutation | 2009 | PMID: 18853459 |
| Dysferlin deficiency shows compensatory induction of Rab27A/Slp2a that may contribute to inflammatory onset. | Kesari A | The American journal of pathology | 2008 | PMID: 18832576 |
| Dysferlinopathy in the Jews of the Caucasus: a frequent mutation in the dysferlin gene. | Leshinsky-Silver E | Neuromuscular disorders : NMD | 2007 | PMID: 17825554 |
| Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. | Nguyen K | Archives of neurology | 2007 | PMID: 17698709 |
| Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies. | Nguyen K | Human mutation | 2005 | PMID: 16010686 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF | - | - | - | - |
Text-mined citations for rs727503909 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 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.
NCBI staff reviewed the sequence information reported in PubMed 17825554 Fig. 2 to determine the location of this allele on the current reference sequence.