ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)

gnomAD frequency: 0.00103  dbSNP: rs28937900
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Total submissions: 43
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000082182 SCV000196820 pathogenic not provided 2020-12-11 criteria provided, single submitter clinical testing 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)
Eurofins Ntd Llc (ga) RCV000082182 SCV000230405 pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing
Invitae RCV000231711 SCV000290704 pathogenic Walker-Warburg congenital muscular dystrophy 2024-01-31 criteria provided, single submitter clinical testing 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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000082182 SCV000510855 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000503787 SCV000594785 pathogenic Muscular dystrophy-dystroglycanopathy 2016-12-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000515332 SCV000611265 pathogenic 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 2022-05-31 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000082182 SCV000613311 pathogenic not provided 2023-02-08 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000612115 SCV000711666 pathogenic Limb-girdle muscular dystrophy 2024-03-11 criteria provided, single submitter clinical testing 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.
Undiagnosed Diseases Network, NIH RCV000004442 SCV000746666 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2017-01-11 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626960 SCV000747663 pathogenic Muscle weakness; Headache; Gait imbalance; Difficulty walking; Paresthesia; Difficulty climbing stairs; Scapular winging; Difficulty standing 2017-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000082182 SCV000885461 pathogenic not provided 2017-07-18 criteria provided, single submitter clinical testing 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)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000004442 SCV001149779 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2019-06-11 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000004442 SCV001164545 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2018-12-03 criteria provided, single submitter research 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).
Myriad Genetics, Inc. RCV000004442 SCV001193780 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2019-12-17 criteria provided, single submitter clinical testing 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.
CeGaT Center for Human Genetics Tuebingen RCV000082182 SCV001250133 pathogenic not provided 2023-08-01 criteria provided, single submitter clinical testing FKRP: PM3:Very Strong, PM2, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001197775 SCV001368554 pathogenic Muscular dystrophy-dystroglycanopathy type B5 2018-10-24 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Institute of Human Genetics, University of Leipzig Medical Center RCV000004442 SCV001429343 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2023-08-17 criteria provided, single submitter clinical testing Criteria applied: PM3_VSTR,PS3
Clinical Genetics and Genomics, Karolinska University Hospital RCV000082182 SCV001449794 likely pathogenic not provided 2015-01-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV001329320 SCV001520726 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 2019-04-07 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000082182 SCV001713825 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526640 SCV001737071 likely pathogenic Myopathy criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000004442 SCV001976888 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2021-10-01 criteria provided, single submitter clinical testing PM2, PP3, PP4, PP5
Revvity Omics, Revvity RCV000082182 SCV002023721 pathogenic not provided 2023-12-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV000004442 SCV002496154 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2022-02-28 criteria provided, single submitter clinical testing ACMG categories: PS1,PS5,PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222338 SCV002500139 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2022-03-06 criteria provided, single submitter clinical testing 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.
AiLife Diagnostics, AiLife Diagnostics RCV000082182 SCV002503339 pathogenic not provided 2020-06-02 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV003993736 SCV002503710 pathogenic Myopathy caused by variation in FKRP 2024-01-05 criteria provided, single submitter clinical testing 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.
MGZ Medical Genetics Center RCV000004442 SCV002580940 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2022-08-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408451 SCV002675707 pathogenic Cardiovascular phenotype 2022-03-16 criteria provided, single submitter clinical testing 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000004442 SCV002767362 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2021-05-06 criteria provided, single submitter clinical testing 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
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000660622 SCV003919964 pathogenic Muscular dystrophy-dystroglycanopathy type B5; Autosomal recessive limb-girdle muscular dystrophy type 2I; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 2021-03-30 criteria provided, single submitter clinical testing 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000004442 SCV004012906 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2023-07-14 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000660622 SCV004035179 pathogenic Muscular dystrophy-dystroglycanopathy type B5; Autosomal recessive limb-girdle muscular dystrophy type 2I; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 2023-08-25 criteria provided, single submitter research
PreventionGenetics, part of Exact Sciences RCV004532287 SCV004732345 pathogenic FKRP-related disorder 2024-02-08 criteria provided, single submitter clinical testing 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.
Clinical Genomics Program, Stanford Medicine RCV001329320 SCV004801383 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 2021-05-21 criteria provided, single submitter clinical testing • 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]
OMIM RCV000004442 SCV000024615 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2012-10-05 no assertion criteria provided literature only
Natera, Inc. RCV000004442 SCV001456653 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000082182 SCV001799747 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000082182 SCV001807166 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000082182 SCV001920442 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000082182 SCV001927663 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000082182 SCV001967570 pathogenic not provided no assertion criteria provided clinical testing
Institute of Human Genetics, University of Wuerzburg RCV000612115 SCV003804453 pathogenic Limb-girdle muscular dystrophy no assertion criteria provided clinical testing

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