ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.826C>A (p.Leu276Ile) (rs28937900)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000082182 SCV000196820 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The L276I variant is the most common pathogenic variant in the FKRP gene and has been reported multiple times in association with FKRP-related disorders (Brockington et al., 2001; Renard et al., 2012; Rasmussen et al., 2014). In vitro studies showed that the L276I variant resulted in reduced secretion of the FKRP protein from the cell (Lu et al., 2010). L276I was also reported to cause calf pseudohypertrophy, cardiomyopathy, winged scapula, and elevated creatinine kinase in heterozygous carriers in a single family (Schottlaender et al., 2015). The L276I variant is observed in 130/57750 (0.2%) alleles from individuals of European (non-Finnish) background and in 160/146958 (0.1%) global alleles in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret L276I as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082182 SCV000230405 pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing
Invitae RCV000231711 SCV000290704 pathogenic Walker-Warburg congenital muscular dystrophy 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 276 of the FKRP protein (p.Leu276Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs28937900, ExAC 1.7%). However, the frequency data is considered unreliable due to low coverage of this region of the population database. This variant has been reported to be present at a frequency of 12% in the Hutterite general population and at 0.3% in the European general population (PMID: 15580560, 22981120). This variant is a well known limb girdle muscular dystrophy (LGMD2I) causative allele. It is a founder mutation in the Hutterite population and the most common cause of LGMD2I in the Northern European population (PMID: 11741828, 15580560). This variant has been reported in LGMD2I patients with a broad spectrum of disease, including individuals with cardiac involvement (PMID: 14647208, 21220724, 16786213, 18639457, 23576288, 15580560, 18060779). ClinVar contains an entry for this variant (Variation ID: 4221). Experimental studies have shown that this variant impairs protein function (PMID: 11741828, 15580560, 23591631). Additionally, this variant has been found to have an effect on muscle function in a mouse model (PMID: 23591631). In summary, this variant is a rare missense change that is a known founder variant and has been shown to disrupt protein function. For these reasons, it 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 A, 1; Congenital muscular dystrophy-dystroglycanopathy (with or without mental retardation) type B5; Limb-girdle muscular dystrophy-dystroglycanopathy, type C5; Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A5 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000082182 SCV000613311 pathogenic not provided 2015-10-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000612115 SCV000711666 pathogenic Limb-girdle muscular dystrophy 2017-10-03 criteria provided, single submitter clinical testing The p.Leu276Ile variant in FKRP is a well-established pathogenic variant for lim b girdle muscular dystrophy (LGMD) (Walter 2004, Frosk 2005, Sveen 2006, Rasmuss en 2014, LMM data). This variant is a founder mutation in the Hutterite populati on (Frosk 2005), and has been identified in 0.2% (130/57750) of European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g/; dbSNP rs28937900). Additionally, mouse models carrying this variant in the h omozygous state support that this variant causes disease (Krag 2015). In summary , this variant meets criteria to be classified as pathogenic for LGMD in an auto somal recessive manner. ACMG/AMP Criteria applied: PM3_Strong, PS3.
Undiagnosed Diseases Network,NIH RCV000004442 SCV000746666 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 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
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000660622 SCV000782740 pathogenic Congenital muscular dystrophy-dystroglycanopathy (with or without mental retardation) type B5; Limb-girdle muscular dystrophy-dystroglycanopathy, type C5; Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A5 2017-09-21 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,Klinikum rechts der Isar RCV000004442 SCV001149779 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 2019-06-11 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000004442 SCV001164545 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 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 Women's Health, Inc. RCV000004442 SCV001193780 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 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 Praxis fuer Humangenetik Tuebingen RCV000082182 SCV001250133 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197775 SCV001368554 pathogenic Polymicrogyria; Abnormality of neuronal migration 2018-10-24 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000004442 SCV001429343 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 2019-11-22 criteria provided, single submitter clinical testing This variant was identified as homozygous
OMIM RCV000004442 SCV000024615 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 2012-10-05 no assertion criteria provided literature only

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