This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:18276788). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:18276788) (PMID:14678801).
ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)
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.
(15)
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
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Genotype
- Identifiers
-
NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)
Variation ID: 242418 Accession: VCV000242418.61
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.2 2: 71570680 (GRCh38) [ NCBI UCSC ] 2: 71797810 (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 Jul 2, 2017 Oct 26, 2024 Feb 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130987.2:c.3167G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Arg1056Gln missense NM_003494.4:c.3113G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Arg1038Gln missense NM_001130455.2:c.3116G>A NP_001123927.1:p.Arg1039Gln missense NM_001130976.2:c.3071G>A NP_001124448.1:p.Arg1024Gln missense NM_001130977.2:c.3071G>A NP_001124449.1:p.Arg1024Gln missense NM_001130978.2:c.3113G>A NP_001124450.1:p.Arg1038Gln missense NM_001130979.2:c.3206G>A NP_001124451.1:p.Arg1069Gln missense NM_001130980.2:c.3164G>A NP_001124452.1:p.Arg1055Gln missense NM_001130981.2:c.3164G>A NP_001124453.1:p.Arg1055Gln missense NM_001130982.2:c.3209G>A NP_001124454.1:p.Arg1070Gln missense NM_001130983.2:c.3116G>A NP_001124455.1:p.Arg1039Gln missense NM_001130984.2:c.3074G>A NP_001124456.1:p.Arg1025Gln missense NM_001130985.2:c.3167G>A NP_001124457.1:p.Arg1056Gln missense NM_001130986.2:c.3074G>A NP_001124458.1:p.Arg1025Gln missense NC_000002.12:g.71570680G>A NC_000002.11:g.71797810G>A NG_008694.1:g.122058G>A LRG_845:g.122058G>A LRG_845t1:c.3113G>A LRG_845p1:p.Arg1038Gln LRG_845t2:c.3167G>A LRG_845p2:p.Arg1056Gln O75923:p.Arg1038Gln - Protein change
- R1038Q, R1056Q, R1024Q, R1055Q, R1069Q, R1070Q, R1025Q, R1039Q
- Other names
-
NM_001130455.1(DYSF):c.3116G>A(p.Arg1039Gln)
NM_001130976.1(DYSF):c.3071G>A(p.Arg1024Gln)
NM_001130977.1(DYSF):c.3071G>A(p.Arg1024Gln)
NM_001130978.1(DYSF):c.3113G>A(p.Arg1038Gln)
NM_001130979.1(DYSF):c.3206G>A(p.Arg1069Gln)
NM_001130980.1(DYSF):c.3164G>A(p.Arg1055Gln)
NM_001130981.1(DYSF):c.3164G>A(p.Arg1055Gln)
NM_001130982.1(DYSF):c.3209G>A(p.Arg1070Gln)
NM_001130983.1(DYSF):c.3116G>A(p.Arg1039Gln)
NM_001130984.1(DYSF):c.3074G>A(p.Arg1025Gln)
NM_001130985.1(DYSF):c.3167G>A(p.Arg1056Gln)
NM_001130986.1(DYSF):c.3074G>A(p.Arg1025Gln)
NM_001130987.1(DYSF):c.3167G>A(p.Arg1056Gln)
NM_003494.3(DYSF):c.3113G>A(p.Arg1038Gln)
- Canonical SPDI
- NC_000002.12:71570679:G:A
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00001
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 7, 2021 | RCV000493116.39 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 7, 2023 | RCV000555598.19 | |
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV000596380.14 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Mar 21, 2019 | RCV001196058.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 22, 2024 | RCV003469174.2 |
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
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803534.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 … (more)
This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:18276788). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:18276788) (PMID:14678801). (less)
|
|
|
Pathogenic
(Apr 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000701408.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Jan 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582561.4
First in ClinVar: Jul 02, 2017 Last updated: Apr 17, 2019 |
Comment:
The R1038Q pathogenic variant has been previously observed in multiple unrelated individuals with DYSF-related disorders, who harbored an additional DYSF variant, referred for genetic testing … (more)
The R1038Q pathogenic variant has been previously observed in multiple unrelated individuals with DYSF-related disorders, who harbored an additional DYSF variant, referred for genetic testing at GeneDx and in the published literature (Cagliani et al., 2003; Krahn et al., 2009). Western blot analysis and immunohistochemistry demonstrated individuals harboring R1038Q had reduced dysferlin (Cagliani et al., 2003; Xi et al., 2014; Nagaraju et al., 2008). The R1038Q variant is observed in 11/111,482 (0.01%) alleles from individuals of European background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret R1038Q as a pathogenic variant. (less)
|
|
|
Pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Dysferlinopathy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914939.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including … (more)
The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including one homozygote, four presumed compound heterozygotes, one patient where four other variants in this gene were also identified, one heterozygote, and two patients in whom the genotypes were not specified (Cagliani et al. 2003; Nagaraju et al. 2008; Krahn et al. 2009; Xi et al. 2014; Shin et al. 2015 and Quinn et al. 2016). The p.Arg1038Gln variant was absent from 300 control chromosomes and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of protein from muscle tissue revealed 4% residual dysferlin compared to wild type (Cagliani et al. 2003). Based on the collective evidence, the p.Arg1038Gln variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Mar 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Distal myopathy with anterior tibial onset
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366487.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state.
|
|
|
Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841344.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Protein truncation variants are a common disease-causing … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000242418). A different missense change at the same codon (p.Arg1056Pro) has been reported to be associated with DYSF related disorder (PMID: 33610434). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Scoliosis (present) , Elevated circulating creatine kinase concentration (present) , Elevated circulating hepatic transaminase concentration (present) , Calf muscle hypertrophy (present) , Foot dorsiflexor weakness … (more)
Scoliosis (present) , Elevated circulating creatine kinase concentration (present) , Elevated circulating hepatic transaminase concentration (present) , Calf muscle hypertrophy (present) , Foot dorsiflexor weakness (present) , Flexion contracture (present) (less)
|
|
|
Pathogenic
(Dec 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021878.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 07, 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: SCV000649653.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). This variant is present in population databases (rs150877497, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This variant is also known as p.Arg1056Gln. ClinVar contains an entry for this variant (Variation ID: 242418). 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) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 27821570). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194203.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Dec 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780666.29
First in ClinVar: Jul 02, 2017 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Nov 02, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132178.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035547.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037438.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Aug 12, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002082260.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Distal myopathy with anterior tibial onset
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091514.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
|
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Comment:
Comment:
The R1038Q pathogenic variant has been previously observed in multiple unrelated individuals with DYSF-related disorders, who harbored an additional DYSF variant, referred for genetic testing at GeneDx and in the published literature (Cagliani et al., 2003; Krahn et al., 2009). Western blot analysis and immunohistochemistry demonstrated individuals harboring R1038Q had reduced dysferlin (Cagliani et al., 2003; Xi et al., 2014; Nagaraju et al., 2008). The R1038Q variant is observed in 11/111,482 (0.01%) alleles from individuals of European background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret R1038Q as a pathogenic variant.
Comment:
The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including one homozygote, four presumed compound heterozygotes, one patient where four other variants in this gene were also identified, one heterozygote, and two patients in whom the genotypes were not specified (Cagliani et al. 2003; Nagaraju et al. 2008; Krahn et al. 2009; Xi et al. 2014; Shin et al. 2015 and Quinn et al. 2016). The p.Arg1038Gln variant was absent from 300 control chromosomes and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of protein from muscle tissue revealed 4% residual dysferlin compared to wild type (Cagliani et al. 2003). Based on the collective evidence, the p.Arg1038Gln variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000242418). A different missense change at the same codon (p.Arg1056Pro) has been reported to be associated with DYSF related disorder (PMID: 33610434). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). This variant is present in population databases (rs150877497, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This variant is also known as p.Arg1056Gln. ClinVar contains an entry for this variant (Variation ID: 242418). 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) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 27821570). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:18276788). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:18276788) (PMID:14678801).
Comment:
The R1038Q pathogenic variant has been previously observed in multiple unrelated individuals with DYSF-related disorders, who harbored an additional DYSF variant, referred for genetic testing at GeneDx and in the published literature (Cagliani et al., 2003; Krahn et al., 2009). Western blot analysis and immunohistochemistry demonstrated individuals harboring R1038Q had reduced dysferlin (Cagliani et al., 2003; Xi et al., 2014; Nagaraju et al., 2008). The R1038Q variant is observed in 11/111,482 (0.01%) alleles from individuals of European background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret R1038Q as a pathogenic variant.
Comment:
The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including one homozygote, four presumed compound heterozygotes, one patient where four other variants in this gene were also identified, one heterozygote, and two patients in whom the genotypes were not specified (Cagliani et al. 2003; Nagaraju et al. 2008; Krahn et al. 2009; Xi et al. 2014; Shin et al. 2015 and Quinn et al. 2016). The p.Arg1038Gln variant was absent from 300 control chromosomes and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of protein from muscle tissue revealed 4% residual dysferlin compared to wild type (Cagliani et al. 2003). Based on the collective evidence, the p.Arg1038Gln variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000242418). A different missense change at the same codon (p.Arg1056Pro) has been reported to be associated with DYSF related disorder (PMID: 33610434). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). This variant is present in population databases (rs150877497, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This variant is also known as p.Arg1056Gln. ClinVar contains an entry for this variant (Variation ID: 242418). 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) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. Experimental studies have shown that this missense change affects DYSF function (PMID: 27821570). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease. | Moore U | Neuromuscular disorders : NMD | 2021 | PMID: 33610434 |
| Clinical Reasoning: A 30-year-old man with progressive weakness and atrophy. | Quinn C | Neurology | 2016 | PMID: 27821570 |
| Targeted next-generation sequencing for the genetic diagnosis of dysferlinopathy. | Shin HY | Neuromuscular disorders : NMD | 2015 | PMID: 25868377 |
| Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy. | Xi J | Neurology India | 2014 | PMID: 25591676 |
| Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies. | Ankala A | Muscle & nerve | 2014 | PMID: 24488599 |
| 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 |
| Dysferlin deficiency enhances monocyte phagocytosis: a model for the inflammatory onset of limb-girdle muscular dystrophy 2B. | Nagaraju K | The American journal of pathology | 2008 | PMID: 18276788 |
| Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effect in the Italian population. | Cagliani R | Neuromuscular disorders : NMD | 2003 | PMID: 14678801 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF | - | - | - | - |
Text-mined citations for rs150877497 ...
HelpThese citations are identified by LitVar using
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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.