ClinVar Genomic variation as it relates to human health
NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)
Variation ID: 4221 Accession: VCV000004221.87
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 46756276 (GRCh38) [ NCBI UCSC ] 19: 47259533 (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 Aug 4, 2024 Jul 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_024301.5:c.826C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077277.1:p.Leu276Ile missense NM_001039885.3:c.826C>A NP_001034974.1:p.Leu276Ile missense NC_000019.10:g.46756276C>A NC_000019.9:g.47259533C>A NG_008898.2:g.15231C>A LRG_761:g.15231C>A LRG_761t1:c.826C>A LRG_761p1:p.Leu276Ile Q9H9S5:p.Leu276Ile - Protein change
- L276I
- Other names
- FKRP, LEU276ILE (rs28937900)
- p.L276I:CTA>ATA
- Canonical SPDI
- NC_000019.10:46756275:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00102
The Genome Aggregation Database (gnomAD), exomes 0.00103
Exome Aggregation Consortium (ExAC) 0.00396
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 | ||
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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. |
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FKRP | - | - |
GRCh38 GRCh37 |
1047 | 1089 |
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. |
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Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2023 | RCV000004442.34 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000231711.19 | |
Pathogenic (2) |
criteria provided, single submitter
|
Mar 11, 2024 | RCV000612115.14 | |
Pathogenic/Likely pathogenic (15) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000082182.63 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 25, 2023 | RCV000660622.14 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 20, 2016 | RCV000503787.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 31, 2022 | RCV000515332.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626960.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV001329320.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 24, 2018 | RCV001197775.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2022 | RCV002222338.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 16, 2022 | RCV002408451.9 | |
FKRP-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2024 | RCV004532287.1 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV003993736.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001526640.10 | |
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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. |
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Pathogenic
(Dec 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000594785.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
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Pathogenic
(Jan 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
Female siblings found to have 2
(more...)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746666.1 First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
Number of individuals with the variant: 2
Clinical Features:
Vertigo (present) , Tinnitus (present) , Scoliosis (present) , Rhabdomyolysis (present) , Postural hypotension with compensatory tachycardia (present) , Paresthesia (present) , Palpitations (present) , … (more)
Vertigo (present) , Tinnitus (present) , Scoliosis (present) , Rhabdomyolysis (present) , Postural hypotension with compensatory tachycardia (present) , Paresthesia (present) , Palpitations (present) , Pain (present) , Myopia (present) , Memory impairment (present) , Joint hypermobility (present) , Hyperextensible skin of face (present) , Heat intolerance (present) , Gait imbalance (present) , Exercise-induced myoglobinuria (present) , Elevated serum creatine phosphokinase (present) , Elevated aldolase level (present) , Dyspnea (present) , Chronic fatigue (present) , Arachnodactyly (present) , Abnormal EKG (present) (less)
Family history: yes
Age: 25-30 years
Sex: female
Ethnicity/Population group: White
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2017-01-11
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Jul 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885461.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019 |
Comment:
The p.Leu276Ile variant is the most frequently observed variant in limb girdle muscular dystrophy 2I (LGMD2I) and is predicted to be a founder variant of … (more)
The p.Leu276Ile variant is the most frequently observed variant in limb girdle muscular dystrophy 2I (LGMD2I) and is predicted to be a founder variant of European origin (Brockington et al. 2001, Hanisch et al. 2010, and Frosk et al. 2005). Functional in vitro studies show that the p.Leu276Ile variant decreases the secretion of FKRP protein (Lu et al. 2010). In a 10 patient cohort, all homozygous for the p.Leu276Ile variant, patients displayed reduced left ventricle ejection fractions and reduced stoke volume but did not have left ventricle hypertrophy (Hollingsworth et al. 2013). This variant is listed multiple times as a pathogenic variant in ClinVar (see link below) and meets our criteria to be classified as a pathogenic variant. Pathogenic variants of FKRP are inherited in an autosomal recessive manner and are associated with Muscular dystrophy-dystroglycanopathy, types A5, B5 and C5 (MIM: 613153, 606612, and 607155).Thus, this patient is at least a carrier. However, our analysis cannot detect variants in deep intronic or enhancer regions; therefore, the presence of additional pathogenic variants in these regions cannot be excluded. Symptomatic heterozygous carriers have been reported at least once in literature and present with a milder phenotype. (Schottlaender et al. 2015) (less)
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Pathogenic
(Jan 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000230405.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 149
Sex: mixed
|
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Pathogenic
(Jun 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149779.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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Autosomal recessive limb-girdle muscular dystrophy type 2I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164545.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The homozygous p.Leu276Ile variant in FKRP was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in … (more)
The homozygous p.Leu276Ile variant in FKRP was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.1089% (160/146958) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28937900). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies provide some evidence that the p.Leu276Ile variant may impact protein function (PMID: 11741828, 15580560, 23591631). However, these types of assays may not accurately represent biological function.There are many reports of individuals with limb-girdle muscular dystrophy that are homozygous or compound heterozygous for the variant in ClinVar and the literature. In summary, the clinical significance of the p.Leu276Ile variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS3, PM3_Strong, PP3 (Richards 2015). (less)
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Likely pathogenic
(Jan 19, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449794.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 21
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Myopathy
Affected status: yes
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737071.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
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Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976888.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM2, PP3, PP4, PP5
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Pathogenic
(Aug 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580940.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM3, PP1, PP3
|
Number of individuals with the variant: 7
Sex: male
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Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767362.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 (MIM#607155). (PMID: 19900540, PMID: 30232282, PMID: 30417025). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to isoleucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (168 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a known founder allele in European populations and it has been reported in multiple homozygous and compound heterozygous individuals with LGMD, usually associated with mild disease (ClinVar, LOVD3, HGMD, OMIM, PMID: 11741828, PMID: 15580560, PMID: 14647208). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign (less)
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Pathogenic
(May 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
Muscular dystrophy-dystroglycanopathy type B5 Autosomal recessive limb-girdle muscular dystrophy type 2I Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611265.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Aug 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429343.2
First in ClinVar: Aug 17, 2020 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PM3_VSTR,PS3
Clinical Features:
Foot pain (present) , Muscular dystrophy (present) , Exercise intolerance (present) , Extremely elevated creatine kinase (present)
Sex: female
|
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Pathogenic
(Aug 25, 2023)
|
criteria provided, single submitter
Method: research
|
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Muscular dystrophy-dystroglycanopathy type B5 Autosomal recessive limb-girdle muscular dystrophy type 2I
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV004035179.1 First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Fatigue (present) , Arthralgia (present) , Scoliosis (present) , Pes planus (present) , Tremor (present) , Cerebellar ataxia (present) , Myopia (present)
|
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Pathogenic
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713825.4
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Number of individuals with the variant: 14
|
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Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023721.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Walker-Warburg congenital muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000290704.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 276 of the FKRP protein (p.Leu276Ile). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 276 of the FKRP protein (p.Leu276Ile). This variant is present in population databases (rs28937900, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 14647208, 16786213, 18060779, 18639457, 21220724, 23576288). It is commonly reported in individuals of Northern European ancestry (PMID: 11741828, 15580560). ClinVar contains an entry for this variant (Variation ID: 4221). 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 FKRP protein function. Experimental studies have shown that this missense change affects FKRP function (PMID: 11741828, 15580560, 23591631). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
FKRP-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004732345.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The FKRP c.826C>A variant is predicted to result in the amino acid substitution p.Leu276Ile. This variant is well documented in many individuals with autosomal recessive … (more)
The FKRP c.826C>A variant is predicted to result in the amino acid substitution p.Leu276Ile. This variant is well documented in many individuals with autosomal recessive limb girdle muscular dystrophy type 2I and is one of the most common pathogenic variants in FKRP (Brockington et al. 2001. PubMed ID: 11741828; Walter et al. 2004. PubMed ID: 15060126; http://www.LOVD.nl/FKRP). This variant is reported in 0.23% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Myopathy caused by variation in FKRP
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503710.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change in FKRP is predicted to replace leucine with isoleucine at codon 276, p.(Leu276Ile). The leucine residue is weakly conserved (100 vertebrates, UCSC), … (more)
This sequence change in FKRP is predicted to replace leucine with isoleucine at codon 276, p.(Leu276Ile). The leucine residue is weakly conserved (100 vertebrates, UCSC), and is located in the lumenal domain. There is a small physicochemical difference between leucine and isoleucine. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.2% (136/67,802 alleles) in the European (non-Finnish) population, and is a European founder variant for limb-girdle muscular dystrophy (PMID: 15580560). The variant has been identified homozygous and compound heterozygous with a second pathogenic allele in multiple cases with limb-girdle muscular dystrophy, and segregates with the condition in multiple families (PMID: 11741828, 15580560). Additionally, knock-in mouse models of the variant recapitulate the human phenotype (PMID: 23591631, 26574668). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.70). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong, PP3. (less)
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Pathogenic
(Mar 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Limb-girdle muscular dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711666.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Leu276Ile variant in FKRP has been reported in the homozygous or compound heterozygous state in >10 individuals with limb-girdle muscular dystrophy (LGMD) (Brockington 2001 … (more)
The p.Leu276Ile variant in FKRP has been reported in the homozygous or compound heterozygous state in >10 individuals with limb-girdle muscular dystrophy (LGMD) (Brockington 2001 PMID: 11741828; Walter 2004 PMID: 15060126). This variant is considered to be a founder mutation within the Hutterite population (Frosk 2005 PMID:15580560) and has been identified in 0.2% (2820/1135906) of European chromosomes by gnomAD, including 2 homozygous individuals (http://gnomad.broadinstitute.org). Affected individuals may not be reliably excluded from the gnomAD database given that FKRP-related LGMD (type 2I) is typically a milder form of disease and onset is typically in adulthood. This variant has also been reported in ClinVar (Variation ID: 4221). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Animal models in mice have shown that this variant causes limb-girdle muscular dystrophy (Krag 2015 PMID: 26574668). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive LGMD. ACMG/AMP Criteria applied: PM3_Very Strong, PS3, PP3. (less)
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Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250133.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Comment:
FKRP: PM3:Very Strong, PM2, PP3, PS3:Supporting
Number of individuals with the variant: 30
|
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Pathogenic
(Feb 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510855.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
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Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Difficulty climbing stairs
Difficulty standing Difficulty walking Gait imbalance Headache Muscle weakness Paresthesia Scapular winging
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747663.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
|
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Pathogenic
(Dec 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193780.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_024301.4(FKRP):c.826C>A(L276I) is classified as pathogenic in the context of FKRP-related disorders. Sources cited for classification include the following: PMID 15574464, 23591631, 19900540, 11741828 and 18639457. … (more)
NM_024301.4(FKRP):c.826C>A(L276I) is classified as pathogenic in the context of FKRP-related disorders. Sources cited for classification include the following: PMID 15574464, 23591631, 19900540, 11741828 and 18639457. Classification of NM_024301.4(FKRP):c.826C>A(L276I) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Oct 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy type B5
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368554.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
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Pathogenic
(Dec 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000196820.13
First in ClinVar: Jan 28, 2015 Last updated: Jul 18, 2021 |
Comment:
Reported to cause calf pseudohypertrophy, cardiomyopathy, winged scapula, and elevated creatinine kinase in heterozygous carriers in a single family (Schottlaender et al., 2015); Published functional … (more)
Reported to cause calf pseudohypertrophy, cardiomyopathy, winged scapula, and elevated creatinine kinase in heterozygous carriers in a single family (Schottlaender et al., 2015); Published functional studies demonstrate a damaging effect, suggesting that this variant results in reduced secretion of protein from the cell (Lu et al., 2010); Homozygous mouse knock-in model demonstrated the classic late-onset LGMD2I phenotype in both skeletal and cardiac muscles (Qiao et al., 2014); This variant is associated with the following publications: (PMID: 31127727, 32914449, 31980526, 32429923, 32403337, 32190976, 31268217, 30919934, 30564623, 29858056, 19900540, 15883334, 28112097, 19705481, 15886712, 16634037, 16786213, 18639457, 22981120, 21220724, 18060779, 23891399, 29545481, 30232282, 30060766, 29970176, 14647208, 25560911, 11741828, 28479227, 15060126, 28107841, 28666318, 26833294, 26363967, 26574668, 25048216, 17554798, 15574464, 23591631, 16344347, 21228398, 19820980, 15580560, 23576288, 12666124, 18593008, 24447024, 22264518, 31041397, 32042916) (less)
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Pathogenic
(Feb 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002496154.1
First in ClinVar: Apr 11, 2022 Last updated: Apr 11, 2022 |
Comment:
ACMG categories: PS1,PS5,PM2
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(Mar 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500139.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: FKRP c.826C>A (p.Leu276Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: FKRP c.826C>A (p.Leu276Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 121630 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.001 vs 0.0024), allowing no conclusion about variant significance. c.826C>A has been widely reported in the literature as a founder mutation in Hutterite and European populations observed as homozygous and compound heterozygous genotypes in multiple individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy (example, Brockington_2001). These data indicate that the variant is very likely to be associated with disease. Several studies report experimental evidence evaluating an impact on protein function and demonstrate reduced alpha-dystroglycan glycosylation in animal models consistent with the pathophysiology of disease (example, Blaeser_2013). More recently, utilizing cell lines harboring this variant, defective autophagy-lysosome pathway and increased apoptosis have been shown to contribute towards the pathogenesis of FKRP-associated muscular dystrophies (example, Ortiz-Cordero_2021). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503339.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy type B5
Autosomal recessive limb-girdle muscular dystrophy type 2I Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003919964.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
FKRP NM_024301.4 exon 4 p.Leu276Ile (c.826C>A): This variant is a well reported and established mutation in the literature, identified in several individuals with Limb-Girdle Muscular … (more)
FKRP NM_024301.4 exon 4 p.Leu276Ile (c.826C>A): This variant is a well reported and established mutation in the literature, identified in several individuals with Limb-Girdle Muscular Dystrophy Type 2I, in the homozygous and compound heterozygous state, including an entry in GeneReviews (Brockington 2001 PMID:11741828, Frosk 2005 PMID:15580560, Pegoaro 2012 PMID:20301582, Alhamidi 2017 PMID:28479227). This variant is present in 0.2% (130/57750) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28937900). In addition, this variant is known to be a founder mutation and has been identified at increased frequency in the Hutterite population (Frosk 2005 PMID:15580560). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:4221). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies, including a mouse model, predict that this variant will impact the protein, suggestive of the progressive loss of α-dystroglycan specific glycosylation (Krag 2015 PMID:26574668). In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004012906.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Clinical Features:
Migraine without aura (present) , Elevated circulating creatinine concentration (present)
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Pathogenic
(Feb 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000613311.5
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant accounts for the vast majority of LGMD2I cases in northern Europe and populations of northern European descent, therefore this variant in the general … (more)
This variant accounts for the vast majority of LGMD2I cases in northern Europe and populations of northern European descent, therefore this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org) (PMID: 15060126, 20961759). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19900540) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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Pathogenic
(May 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Stanford Medicine
Accession: SCV004801383.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
• The p.Leu276Ile variant in the FKRP gene is the most commonly identified variant among individuals of European ancestry affected with limb girdle muscular dystrophy … (more)
• The p.Leu276Ile variant in the FKRP gene is the most commonly identified variant among individuals of European ancestry affected with limb girdle muscular dystrophy R9, and is recognized as a founder mutation in the Hutterite population (Frosk et al., 2005; Murphy et al., 2020). • Individuals homozygous for the p.Leu276Ile variant are observed to have a milder phenotype with later onset of disease (Murphy et al., 2020). • Two related heterozygous carriers of the p.Leu276Ile variant were reported to manifest symptoms of disease including muscle hypertrophy, elevated serum CK, and cardiomyopathy (Schottlaender et al., 2015); however, given the high frequency of this variant and lack of additional reports, risk of manifesting disease in heterozygous carriers has not been convincingly demonstrated. • This variant has been identified in 139/60,758 European (non-Finnish) chromosomes (168/152,176 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Functional studies of the p.Leu276Ile variant are supportive of a deleterious effect to the protein (Lu et al., 2010), and a homozygous mouse model demonstrated a similar disease phenotype and progression as observed in humans (Krag and Vissing, 2015). • Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu276Ile variant as pathogenic for autosomal recessive FKRP-related muscular dystrophy-dystroglycanopathy. [ACMG evidence codes used: PM3_Very Strong; PS3; PP3] (less)
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Pathogenic
(Mar 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002675707.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L276I pathogenic mutation (also known as c.826C>A), located in coding exon 1 of the FKRP gene, results from a C to A substitution at … (more)
The p.L276I pathogenic mutation (also known as c.826C>A), located in coding exon 1 of the FKRP gene, results from a C to A substitution at nucleotide position 826. The leucine at codon 276 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in the homozygous and compound heterozygous states in numerous patients with limb girdle muscular dystrophy (LGMD) and is the most common pathogenic variant detected in the FKRP gene (e.g., Brockington M et al. Hum. Mol. Genet., 2001 Dec;10:2851-9; Boito CA et al. Arch. Neurol., 2005 Dec;62:1894-9; Sveen ML et al. Ann. Neurol., 2006 May;59:808-15; Alhamidi M et al. Neuromuscul. Disord., 2017 Jul;27:619-626). This alteration has been shown to be a founder mutation in the Hutterite and German populations (Walter MC et al. J. Med. Genet., 2004 Apr;41:e50; Frosk P et al. Hum. Mutat., 2005 Jan;25:38-44). Functional studies indicate that this variant results in reduced FKRP secretion, and mice homozygous for this alteration develop progressive myopathy in skeletal and cardiac muscle (Lu PJ et al. Biochim. Biophys. Acta, 2010 Feb;1802:253-8; Qiao C et al. Mol. Ther., 2014 Nov;22:1890-9; Krag TO et al. J. Neuropathol. Exp. Neurol., 2015 Dec;74:1137-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 27, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520726.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
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Pathogenic
(Oct 05, 2012)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024615.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2018 |
Comment on evidence:
In 15 of 17 families with autosomal recessive limb-girdle muscular dystrophy (MDDGC5; 607155), Brockington et al. (2001) found homozygosity or compound heterozygosity for an 826C-A … (more)
In 15 of 17 families with autosomal recessive limb-girdle muscular dystrophy (MDDGC5; 607155), Brockington et al. (2001) found homozygosity or compound heterozygosity for an 826C-A transversion in the FKRP gene, predicted to result in a substitution of isoleucine for leucine 276 (L276I). Patients with the L276I change had the clinically less severe phenotype, suggesting that this is a less disruptive FKRP mutation than those found in patients with MDDGB5; see, e.g., 606596.0001. Mercuri et al. (2003) reported a patient with limb-girdle muscular dystrophy who was compound heterozygous for 2 mutations in the FKRP gene: L276I and Y307N (606596.0016). The patient had an unusually severe form of the disorder and died in his early teens. De Paula et al. (2003) identified the L276I mutation in 9 of 26 mutated alleles among 13 Brazilian families with LGMD (MDDGC5). In affected members of 5 Hutterite families with autosomal recessive LGMD, Frosk et al. (2005) identified homozygosity for the L276I mutation. A single common haplotype surrounding the FKRP gene was identified in the Hutterite LGMD patients, and an identical core haplotype was also found in 19 other non-Hutterite LGMD patients from Europe, Canada, and Brazil, carrying the L276I mutation. This finding indicated that the L276I dispersed from populations of European origin. Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the L276I mutation and an LGMD2H (LGMDR8; 254110)-related TRIM32 mutation (D487N; 602290.0001). Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated disease. Both parents and 3 other sibs were carriers of the L276I mutation and homozygous for the D487N mutation, with highly variable phenotypic expression. Sveen et al. (2006) identified the L276I mutation in 38 Danish patients with LGMD, of whom 27 were homozygous, and 11 were compound heterozygous with another pathogenic FKRP mutation. The variant was detected in 1 of 200 control alleles. Among 1,127 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 121 heterozygotes and 3 homozygotes for the L276I mutation in the FKRP gene, for a frequency of 0.107, or 1 in 9.5. The carrier frequency in other populations is 1 in 300 (Frosk et al., 2005). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920442.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927663.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967570.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Wuerzburg
Accession: SCV003804453.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001456653.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799747.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807166.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies. | Ortiz-Cordero C | Stem cell reports | 2021 | PMID: 34653404 |
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
Functional and cellular localization diversity associated with Fukutin-related protein patient genetic variants. | Henriques SF | Human mutation | 2019 | PMID: 31268217 |
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. | Ten Dam L | Clinical genetics | 2019 | PMID: 30919934 |
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice. | Vannoy CH | Molecular therapy. Methods & clinical development | 2018 | PMID: 30417025 |
A limb-girdle muscular dystrophy 2I model of muscular dystrophy identifies corrective drug compounds for dystroglycanopathies. | Serafini PR | JCI insight | 2018 | PMID: 30232282 |
Limb girdle muscular dystrophy type 2I: No correlation between clinical severity, histopathology and glycosylated α-dystroglycan levels in patients homozygous for common FKRP mutation. | Alhamidi M | Neuromuscular disorders : NMD | 2017 | PMID: 28479227 |
A novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner patients with a phenotype suggestive of a dystrophinopathy. | Mudau MM | South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde | 2016 | PMID: 28112097 |
An irish case of limb-girdle muscular dystrophy 2I with structural eye involvement. | Yap SM | Muscle & nerve | 2016 | PMID: 26833294 |
Significant response to immune therapies in a case of subacute necrotizing myopathy and FKRP mutations. | Svahn J | Neuromuscular disorders : NMD | 2015 | PMID: 26363967 |
Diagnostic clues and manifesting carriers in fukutin-related protein (FKRP) limb-girdle muscular dystrophy. | Schottlaender LV | Journal of the neurological sciences | 2015 | PMID: 25560911 |
Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery. | Qiao C | Molecular therapy : the journal of the American Society of Gene Therapy | 2014 | PMID: 25048216 |
Clinical and muscle biopsy findings in Norwegian paediatric patients with limb girdle muscular dystrophy 2I. | Rasmussen M | Acta paediatrica (Oslo, Norway : 1992) | 2014 | PMID: 24447024 |
Mouse models of fukutin-related protein mutations show a wide range of disease phenotypes. | Blaeser A | Human genetics | 2013 | PMID: 23591631 |
Subepicardial dysfunction leads to global left ventricular systolic impairment in patients with limb girdle muscular dystrophy 2I. | Hollingsworth KG | European journal of heart failure | 2013 | PMID: 23576288 |
A population-based study of autosomal-recessive disease-causing mutations in a founder population. | Chong JX | American journal of human genetics | 2012 | PMID: 22981120 |
Cortical heterotopia in LGMD2I. | Renard D | Neuromuscular disorders : NMD | 2012 | PMID: 22264518 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Myoglobinuria and muscle pain are common in patients with limb-girdle muscular dystrophy 2I. | Mathews KD | Neurology | 2011 | PMID: 21220724 |
Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with Limb Girdle Muscular Dystrophy 2I. | Stensland E | Neuromuscular disorders : NMD | 2011 | PMID: 20961759 |
Mutations alter secretion of fukutin-related protein. | Lu PJ | Biochimica et biophysica acta | 2010 | PMID: 19900540 |
Frequency of the FKRP mutation c.826C>A in isolated hyperCKemia and in limb girdle muscular dystrophy type 2 in German patients. | Hanisch F | Journal of neurology | 2010 | PMID: 19820980 |
Automated DNA mutation detection using universal conditions direct sequencing: application to ten muscular dystrophy genes. | Bennett RR | BMC genetics | 2009 | PMID: 19835634 |
Cardiac pathology exceeds skeletal muscle pathology in two cases of limb-girdle muscular dystrophy type 2I. | Margeta M | Muscle & nerve | 2009 | PMID: 19705481 |
Cardiac assessment of limb-girdle muscular dystrophy 2I patients: an echography, Holter ECG and magnetic resonance imaging study. | Wahbi K | Neuromuscular disorders : NMD | 2008 | PMID: 18639457 |
Heart transplantation in a child with LGMD2I presenting as isolated dilated cardiomyopathy. | D'Amico A | Neuromuscular disorders : NMD | 2008 | PMID: 18060779 |
Fukutin-related protein localizes to the Golgi apparatus and mutations lead to mislocalization in muscle in vivo. | Keramaris-Vrantsis E | Muscle & nerve | 2007 | PMID: 17554798 |
LGMD 2I due to the common mutation 826C>A in the FKRP gene presenting as myopathy with vacuoles and paired-helical filaments. | Reilich P | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2006 | PMID: 18593008 |
Cardiac involvement in limb-girdle muscular dystrophy 2I : conventional cardiac diagnostic and cardiovascular magnetic resonance. | Gaul C | Journal of neurology | 2006 | PMID: 16786213 |
High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. | Sveen ML | Annals of neurology | 2006 | PMID: 16634037 |
Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. | Boito CA | Archives of neurology | 2005 | PMID: 16344347 |
Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. | Frosk P | European journal of human genetics : EJHG | 2005 | PMID: 15886712 |
LGMD2I presenting with a characteristic Duchenne or Becker muscular dystrophy phenotype. | Schwartz M | Neurology | 2005 | PMID: 15883334 |
Dilated cardiomyopathy may be an early sign of the C826A Fukutin-related protein mutation. | Müller T | Neuromuscular disorders : NMD | 2005 | PMID: 15833432 |
The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. | Frosk P | Human mutation | 2005 | PMID: 15580560 |
Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. | Esapa CT | Human molecular genetics | 2005 | PMID: 15574464 |
FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. | Walter MC | Journal of medical genetics | 2004 | PMID: 15060126 |
Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. | de Paula F | European journal of human genetics : EJHG | 2003 | PMID: 14647208 |
Phenotypic spectrum associated with mutations in the fukutin-related protein gene. | Mercuri E | Annals of neurology | 2003 | PMID: 12666124 |
Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. | Brockington M | Human molecular genetics | 2001 | PMID: 11741828 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKRP | - | - | - | - |
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Text-mined citations for rs28937900 ...
HelpRecord last updated Aug 04, 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.