This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1341 of the DYSF protein (p.Leu1341Pro). This variant is present in population databases (rs757917335, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive dysferlinopathies (PMID: 16705711, 19528035, 22057634, 26436962, 27647186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 23185377, 30292141). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro)
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.
(8)
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro)
Variation ID: 555968 Accession: VCV000555968.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.2 2: 71611481 (GRCh38) [ NCBI UCSC ] 2: 71838611 (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 Aug 5, 2018 Oct 20, 2024 Apr 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130987.2:c.4076T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Leu1359Pro missense NM_003494.4:c.4022T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Leu1341Pro missense NM_001130455.2:c.4025T>C NP_001123927.1:p.Leu1342Pro missense NM_001130976.2:c.3980T>C NP_001124448.1:p.Leu1327Pro missense NM_001130977.2:c.3980T>C NP_001124449.1:p.Leu1327Pro missense NM_001130978.2:c.4022T>C NP_001124450.1:p.Leu1341Pro missense NM_001130979.2:c.4115T>C NP_001124451.1:p.Leu1372Pro missense NM_001130980.2:c.4073T>C NP_001124452.1:p.Leu1358Pro missense NM_001130981.2:c.4073T>C NP_001124453.1:p.Leu1358Pro missense NM_001130982.2:c.4118T>C NP_001124454.1:p.Leu1373Pro missense NM_001130983.2:c.4025T>C NP_001124455.1:p.Leu1342Pro missense NM_001130984.2:c.3983T>C NP_001124456.1:p.Leu1328Pro missense NM_001130985.2:c.4076T>C NP_001124457.1:p.Leu1359Pro missense NM_001130986.2:c.3983T>C NP_001124458.1:p.Leu1328Pro missense NC_000002.12:g.71611481T>C NC_000002.11:g.71838611T>C NG_008694.1:g.162859T>C LRG_845:g.162859T>C LRG_845t1:c.4022T>C LRG_845p1:p.Leu1341Pro LRG_845t2:c.4076T>C LRG_845p2:p.Leu1359Pro - Protein change
- L1341P, L1359P, L1328P, L1342P, L1327P, L1372P, L1358P, L1373P
- Other names
-
p.Leu1359Pro
- Canonical SPDI
- NC_000002.12:71611480:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
variation affecting protein; Variation Ontology [ VariO:0002]
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 2, 2024 | RCV000671892.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 11, 2023 | RCV001247195.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2021 | RCV001531487.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 12, 2024 | RCV004568544.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 30, 2024 | RCV004586866.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000796923.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Pathogenic
(Jul 01, 2019)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
James R Lupski Laboratory, Baylor College Of Medicine
Accession: SCV000930017.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Number of individuals with the variant: 5
Clinical Features:
EMG: myopathic abnormalities (present) , Difficulty climbing stairs (present) , Difficulty running (present) , Proximal muscle weakness (present) , Elevated circulating creatine kinase concentration (present)
Sex: mixed
Ethnicity/Population group: Jordanian
Geographic origin: Jordan
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426530.1
First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020 |
|
|
|
Pathogenic
(Dec 11, 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: SCV001420603.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1341 of the DYSF protein (p.Leu1341Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1341 of the DYSF protein (p.Leu1341Pro). This variant is present in population databases (rs757917335, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive dysferlinopathies (PMID: 16705711, 19528035, 22057634, 26436962, 27647186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 23185377, 30292141). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005060271.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Apr 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005075806.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: DYSF c.4022T>C (p.Leu1341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: DYSF c.4022T>C (p.Leu1341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251292 control chromosomes (gnomAD). c.4022T>C has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Wenzel_2006, Ababneh_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16705711, 34624274). ClinVar contains an entry for this variant (Variation ID: 555968). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005088807.2
First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024 |
Comment:
This variant is predicted to be damaging by in-silico missense prediction tools (REVEL, SIFT and Polyphen2). It was previously reported in patients affected with dysferlinopathies/ … (more)
This variant is predicted to be damaging by in-silico missense prediction tools (REVEL, SIFT and Polyphen2). It was previously reported in patients affected with dysferlinopathies/ limb girdle muscular dystrophy and segregated with disease in a family [PMID: 16705711, 19528035, 22057634, 26436962, 27647186]. This variant has been reported to affect proper folding of the dysferlin C2E domain and it leads to aggregated formation of non-functional protein. [PMID: 23185377, 30292141]. (less)
|
|
|
Pathogenic
(Mar 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001746651.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
Comment:
Comment:
Variant summary: DYSF c.4022T>C (p.Leu1341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251292 control chromosomes (gnomAD). c.4022T>C has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Wenzel_2006, Ababneh_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16705711, 34624274). ClinVar contains an entry for this variant (Variation ID: 555968). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant is predicted to be damaging by in-silico missense prediction tools (REVEL, SIFT and Polyphen2). It was previously reported in patients affected with dysferlinopathies/ limb girdle muscular dystrophy and segregated with disease in a family [PMID: 16705711, 19528035, 22057634, 26436962, 27647186]. This variant has been reported to affect proper folding of the dysferlin C2E domain and it leads to aggregated formation of non-functional protein. [PMID: 23185377, 30292141].
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. |
|---|---|---|---|---|
|
variation affecting protein
|
|
|
James R Lupski Laboratory, Baylor College Of Medicine
Accession: SCV000930017.1
|
|
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1341 of the DYSF protein (p.Leu1341Pro). This variant is present in population databases (rs757917335, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive dysferlinopathies (PMID: 16705711, 19528035, 22057634, 26436962, 27647186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 23185377, 30292141). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: DYSF c.4022T>C (p.Leu1341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251292 control chromosomes (gnomAD). c.4022T>C has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Wenzel_2006, Ababneh_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16705711, 34624274). ClinVar contains an entry for this variant (Variation ID: 555968). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant is predicted to be damaging by in-silico missense prediction tools (REVEL, SIFT and Polyphen2). It was previously reported in patients affected with dysferlinopathies/ limb girdle muscular dystrophy and segregated with disease in a family [PMID: 16705711, 19528035, 22057634, 26436962, 27647186]. This variant has been reported to affect proper folding of the dysferlin C2E domain and it leads to aggregated formation of non-functional protein. [PMID: 23185377, 30292141].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The utility of whole-exome sequencing in accurate diagnosis of neuromuscular disorders in consanguineous families in Jordan. | Ababneh NA | Clinica chimica acta; international journal of clinical chemistry | 2021 | PMID: 34624274 |
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Exon Skipping in a Dysf-Missense Mutant Mouse Model. | Malcher J | Molecular therapy. Nucleic acids | 2018 | PMID: 30292141 |
| Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy. | Hofhuis J | Journal of cell science | 2017 | PMID: 28104817 |
| Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy. | Jin SQ | Chinese medical journal | 2016 | PMID: 27647186 |
| Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. | Ghaoui R | JAMA neurology | 2015 | PMID: 26436962 |
| Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. | Schoewel V | PloS one | 2012 | PMID: 23185377 |
| Ahnak1 abnormally localizes in muscular dystrophies and contributes to muscle vesicle release. | Zacharias U | Journal of muscle research and cell motility | 2011 | PMID: 22057634 |
| Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations. | Cacciottolo M | European journal of human genetics : EJHG | 2011 | PMID: 21522182 |
| New aspects on patients affected by dysferlin deficient muscular dystrophy. | Klinge L | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 19528035 |
| Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). | Fujita E | Human molecular genetics | 2007 | PMID: 17331981 |
| Novel sequence variants in dysferlin-deficient muscular dystrophy leading to mRNA decay and possible C2-domain misfolding. | Wenzel K | Human mutation | 2006 | PMID: 16705711 |
| click to load more click to collapse | ||||
Text-mined citations for rs757917335 ...
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.