The observed stop gained c.3886C>T(p.Gln1296Ter) variant in DYSF gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with limb-girdle muscular dystrophies (LGMD2) (Stehlíková et al., 2014; Rufibach et al., 2023). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (Nguyen et al., 2007). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.3886C>T (p.Gln1296Ter)
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.
(11)
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.
Conflicting classifications of pathogenicity
Pathogenic(7); Uncertain significance(1)
Pathogenic(7); Uncertain significance(1)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001130987.2(DYSF):c.3886C>T (p.Gln1296Ter)
Variation ID: 167025 Accession: VCV000167025.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.2 2: 71600831 (GRCh38) [ NCBI UCSC ] 2: 71827961 (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 Jun 28, 2015 Nov 24, 2024 Mar 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130987.2:c.3886C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Gln1296Ter nonsense NM_003494.4:c.3832C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Gln1278Ter nonsense NM_001130455.2:c.3835C>T NP_001123927.1:p.Gln1279Ter nonsense NM_001130976.2:c.3790C>T NP_001124448.1:p.Gln1264Ter nonsense NM_001130977.2:c.3790C>T NP_001124449.1:p.Gln1264Ter nonsense NM_001130978.2:c.3832C>T NP_001124450.1:p.Gln1278Ter nonsense NM_001130979.2:c.3925C>T NP_001124451.1:p.Gln1309Ter nonsense NM_001130980.2:c.3883C>T NP_001124452.1:p.Gln1295Ter nonsense NM_001130981.2:c.3883C>T NP_001124453.1:p.Gln1295Ter nonsense NM_001130982.2:c.3928C>T NP_001124454.1:p.Gln1310Ter nonsense NM_001130983.2:c.3835C>T NP_001124455.1:p.Gln1279Ter nonsense NM_001130984.2:c.3793C>T NP_001124456.1:p.Gln1265Ter nonsense NM_001130985.2:c.3886C>T NP_001124457.1:p.Gln1296Ter nonsense NM_001130986.2:c.3793C>T NP_001124458.1:p.Gln1265Ter nonsense NC_000002.12:g.71600831C>T NC_000002.11:g.71827961C>T NG_008694.1:g.152209C>T LRG_845:g.152209C>T LRG_845t1:c.3832C>T LRG_845p1:p.Gln1278Ter LRG_845t2:c.3886C>T LRG_845p2:p.Gln1296Ter - Protein change
- Q1278*, Q1296*, Q1264*, Q1310*, Q1295*, Q1265*, Q1279*, Q1309*
- Other names
- -
- Canonical SPDI
- NC_000002.12:71600830:C:T
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
- 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 (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2023 | RCV000323235.19 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV000809801.9 | |
|
DYSF-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 14, 2023 | RCV003917498.3 |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
May 20, 2023 | RCV000984259.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 13, 2024 | RCV003467211.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 15, 2021 | RCV002492572.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331597.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Mar 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194175.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005373711.2
First in ClinVar: Oct 13, 2024 Last updated: Nov 24, 2024 |
Comment:
The observed stop gained c.3886C>T(p.Gln1296Ter) variant in DYSF gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with limb-girdle muscular … (more)
The observed stop gained c.3886C>T(p.Gln1296Ter) variant in DYSF gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with limb-girdle muscular dystrophies (LGMD2) (Stehlíková et al., 2014; Rufibach et al., 2023). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (Nguyen et al., 2007). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the musculoskeletal system (present)
|
|
|
Pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Miyoshi muscular dystrophy 1 Distal myopathy with anterior tibial onset
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002781083.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(May 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021862.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 22, 2024)
|
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: SCV000949977.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1278*) 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.Gln1278*) 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 (rs727503911, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with distal myopathy (PMID: 16010686, 17698709, 25135358). ClinVar contains an entry for this variant (Variation ID: 167025). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001430649.1
First in ClinVar: Aug 22, 2020 Last updated: Aug 22, 2020 |
Comment:
This DYSF variant (rs727503911) is rare (<0.1%) in a large population dataset4 (gnomAD: 4/279112 total alleles; 0.0014%; no homozygotes) and has an entry in ClinVar. … (more)
This DYSF variant (rs727503911) is rare (<0.1%) in a large population dataset4 (gnomAD: 4/279112 total alleles; 0.0014%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a homozygous or compound heterozygous state in individuals affected with LGMDR2 or MMD1. This nonsense variant results in a premature stop codon in exon 34 of 56 likely leading to nonsense?mediated decay and lack of protein production. We consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Apr 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004154967.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
DYSF: PVS1, PM2, PM3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 14, 2023)
|
no assertion criteria provided
Method: clinical testing
|
DYSF-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004736704.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The DYSF c.3832C>T variant is predicted to result in premature protein termination (p.Gln1278*). This variant was reported in individuals with DYSF-related muscular dystrophy (Nguyen et … (more)
The DYSF c.3832C>T variant is predicted to result in premature protein termination (p.Gln1278*). This variant was reported in individuals with DYSF-related muscular dystrophy (Nguyen et al 2005. PubMed ID: 16010686; Klinge et al 2009. PubMed ID: 19528035; Moore et al 2021. PubMed ID: 33610434; Stehlíková et al 2014. PubMed ID: 25135358). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71827961-C-T). Nonsense variants in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Nov 18, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132383.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
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: SCV001462798.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln1278*) 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 (rs727503911, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with distal myopathy (PMID: 16010686, 17698709, 25135358). ClinVar contains an entry for this variant (Variation ID: 167025). For these reasons, this variant has been classified as Pathogenic.
Comment:
This DYSF variant (rs727503911) is rare (<0.1%) in a large population dataset4 (gnomAD: 4/279112 total alleles; 0.0014%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a homozygous or compound heterozygous state in individuals affected with LGMDR2 or MMD1. This nonsense variant results in a premature stop codon in exon 34 of 56 likely leading to nonsense?mediated decay and lack of protein production. We consider this variant to be pathogenic.
Comment:
DYSF: PVS1, PM2, PM3
Comment:
The DYSF c.3832C>T variant is predicted to result in premature protein termination (p.Gln1278*). This variant was reported in individuals with DYSF-related muscular dystrophy (Nguyen et al 2005. PubMed ID: 16010686; Klinge et al 2009. PubMed ID: 19528035; Moore et al 2021. PubMed ID: 33610434; Stehlíková et al 2014. PubMed ID: 25135358). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71827961-C-T). Nonsense variants in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic.
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 observed stop gained c.3886C>T(p.Gln1296Ter) variant in DYSF gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with limb-girdle muscular dystrophies (LGMD2) (Stehlíková et al., 2014; Rufibach et al., 2023). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (Nguyen et al., 2007). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Gln1278*) 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 (rs727503911, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with distal myopathy (PMID: 16010686, 17698709, 25135358). ClinVar contains an entry for this variant (Variation ID: 167025). For these reasons, this variant has been classified as Pathogenic.
Comment:
This DYSF variant (rs727503911) is rare (<0.1%) in a large population dataset4 (gnomAD: 4/279112 total alleles; 0.0014%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a homozygous or compound heterozygous state in individuals affected with LGMDR2 or MMD1. This nonsense variant results in a premature stop codon in exon 34 of 56 likely leading to nonsense?mediated decay and lack of protein production. We consider this variant to be pathogenic.
Comment:
DYSF: PVS1, PM2, PM3
Comment:
The DYSF c.3832C>T variant is predicted to result in premature protein termination (p.Gln1278*). This variant was reported in individuals with DYSF-related muscular dystrophy (Nguyen et al 2005. PubMed ID: 16010686; Klinge et al 2009. PubMed ID: 19528035; Moore et al 2021. PubMed ID: 33610434; Stehlíková et al 2014. PubMed ID: 25135358). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71827961-C-T). Nonsense variants in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Dysferlinopathy. | Adam MP | - | 2021 | PMID: 20301480 |
| Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
| 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 rs727503911 ...
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 Nov 25, 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.