The G1418D pathogenic variant in the DYSF gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with DYSF-related disorders who had decreased or absent dysferlin expression (Rosas-Vargas et al., 2007; Kesari et al., 2008; Nagaraju et al., 2008; Ankala et al., 2014).The G1418D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G1418D as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_001130987.2(DYSF):c.4307G>A (p.Gly1436Asp)
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.
Pathogenic/Likely pathogenic
11
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.4307G>A (p.Gly1436Asp)
Variation ID: 94321 Accession: VCV000094321.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.2 2: 71612726 (GRCh38) [ NCBI UCSC ] 2: 71839856 (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 Nov 24, 2024 Aug 28, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130987.2:c.4307G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124459.1:p.Gly1436Asp missense NM_003494.4:c.4253G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003485.1:p.Gly1418Asp missense NM_001130455.2:c.4256G>A NP_001123927.1:p.Gly1419Asp missense NM_001130976.2:c.4211G>A NP_001124448.1:p.Gly1404Asp missense NM_001130977.2:c.4211G>A NP_001124449.1:p.Gly1404Asp missense NM_001130978.2:c.4253G>A NP_001124450.1:p.Gly1418Asp missense NM_001130979.2:c.4346G>A NP_001124451.1:p.Gly1449Asp missense NM_001130980.2:c.4304G>A NP_001124452.1:p.Gly1435Asp missense NM_001130981.2:c.4304G>A NP_001124453.1:p.Gly1435Asp missense NM_001130982.2:c.4349G>A NP_001124454.1:p.Gly1450Asp missense NM_001130983.2:c.4256G>A NP_001124455.1:p.Gly1419Asp missense NM_001130984.2:c.4214G>A NP_001124456.1:p.Gly1405Asp missense NM_001130985.2:c.4307G>A NP_001124457.1:p.Gly1436Asp missense NM_001130986.2:c.4214G>A NP_001124458.1:p.Gly1405Asp missense NC_000002.12:g.71612726G>A NC_000002.11:g.71839856G>A NG_008694.1:g.164104G>A LRG_845:g.164104G>A LRG_845t1:c.4253G>A LRG_845p1:p.Gly1418Asp LRG_845t2:c.4307G>A LRG_845p2:p.Gly1436Asp - Protein change
- G1418D, G1436D, G1419D, G1404D, G1435D, G1449D, G1450D, G1405D
- Other names
- -
- Canonical SPDI
- NC_000002.12:71612725: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.
-
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
- 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 (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 28, 2024 | RCV000080287.25 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2017 | RCV000177998.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2024 | RCV000536105.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 20, 2024 | RCV003993797.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 25, 2024 | RCV003460751.2 |
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
(Nov 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000795301.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
|
Pathogenic
(Dec 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613210.2
First in ClinVar: Dec 19, 2017 Last updated: Feb 15, 2018 |
|
|
|
Pathogenic
(Sep 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589325.3
First in ClinVar: Mar 24, 2015 Last updated: Feb 15, 2018 |
Comment:
The G1418D pathogenic variant in the DYSF gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with DYSF-related … (more)
The G1418D pathogenic variant in the DYSF gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with DYSF-related disorders who had decreased or absent dysferlin expression (Rosas-Vargas et al., 2007; Kesari et al., 2008; Nagaraju et al., 2008; Ankala et al., 2014).The G1418D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G1418D as a pathogenic variant. (less)
|
|
|
Pathogenic
(Sep 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331195.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 14
Sex: mixed
|
|
|
Pathogenic
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021879.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194173.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Dec 01, 2015)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive limb-girdle muscular dystrophy type 2B
Affected status: yes
Allele origin:
unknown
|
Center for Genetic Medicine Research, Children's National Medical Center
Accession: SCV000265778.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Jan 20, 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: SCV000649686.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1418 of the DYSF protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1418 of the DYSF protein (p.Gly1418Asp). This variant is present in population databases (rs398123787, gnomAD 0.03%). This missense change has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B) (PMID: 18276788, 18294055, 24488599; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 94321). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 20, 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: SCV004813981.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: DYSF c.4253G>A (p.Gly1418Asp) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of … (more)
Variant summary: DYSF c.4253G>A (p.Gly1418Asp) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of 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 4e-05 in 251390 control chromosomes, found exclusively within the Latino subpopulation at a frequency of 0.00029 in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.00029 vs 0.0031), allowing no conclusion about variant significance. c.4253G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy (e.g. Rosas-Vargas_2007, Kesari_2008, Nagaraju_2008, Ankala_2014) . 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: 24488599, 18832576, 18276788, 18294055). ClinVar contains an entry for this variant (Variation ID: 94321). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413447.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1_strong, PP3, PP4, PM1, PM2, PM3_strong, PS4
Number of individuals with the variant: 2
|
|
|
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: SCV001452770.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1418 of the DYSF protein (p.Gly1418Asp). This variant is present in population databases (rs398123787, gnomAD 0.03%). This missense change has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B) (PMID: 18276788, 18294055, 24488599; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 94321). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: DYSF c.4253G>A (p.Gly1418Asp) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of 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 4e-05 in 251390 control chromosomes, found exclusively within the Latino subpopulation at a frequency of 0.00029 in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.00029 vs 0.0031), allowing no conclusion about variant significance. c.4253G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy (e.g. Rosas-Vargas_2007, Kesari_2008, Nagaraju_2008, Ankala_2014) . 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: 24488599, 18832576, 18276788, 18294055). ClinVar contains an entry for this variant (Variation ID: 94321). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP1_strong, PP3, PP4, PM1, PM2, PM3_strong, PS4
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 G1418D pathogenic variant in the DYSF gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with DYSF-related disorders who had decreased or absent dysferlin expression (Rosas-Vargas et al., 2007; Kesari et al., 2008; Nagaraju et al., 2008; Ankala et al., 2014).The G1418D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G1418D as a pathogenic variant.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1418 of the DYSF protein (p.Gly1418Asp). This variant is present in population databases (rs398123787, gnomAD 0.03%). This missense change has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B) (PMID: 18276788, 18294055, 24488599; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 94321). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: DYSF c.4253G>A (p.Gly1418Asp) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of 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 4e-05 in 251390 control chromosomes, found exclusively within the Latino subpopulation at a frequency of 0.00029 in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.00029 vs 0.0031), allowing no conclusion about variant significance. c.4253G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy (e.g. Rosas-Vargas_2007, Kesari_2008, Nagaraju_2008, Ankala_2014) . 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: 24488599, 18832576, 18276788, 18294055). ClinVar contains an entry for this variant (Variation ID: 94321). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP1_strong, PP3, PP4, PM1, PM2, PM3_strong, PS4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Combined sequence and copy number analysis improves diagnosis of limb girdle and other myopathies. | Nallamilli BRR | Annals of clinical and translational neurology | 2023 | PMID: 37688281 |
| Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease. | Moore U | Neuromuscular disorders : NMD | 2021 | PMID: 33610434 |
| Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases. | Punetha J | Journal of neuromuscular diseases | 2016 | PMID: 27854218 |
| Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies. | Ankala A | Muscle & nerve | 2014 | PMID: 24488599 |
| 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 |
| Dysferlin homozygous mutation G1418D causes limb-girdle type 2B in a Mexican family. | Rosas-Vargas H | Genetic testing | 2007 | PMID: 18294055 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF | - | - | - | - |
Text-mined citations for rs398123787 ...
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.