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

gnomAD frequency: 0.00103  dbSNP: rs28937900

Total submissions: 43

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 Inc	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	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	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	RCV000004442	SCV002503710	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2021-03-12	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace leucine with isoleucine at codon 276 of the FKRP protein (p.Leu276Ile). The leucine residue is lowly conserved (100 vertebrates, UCSC), and is located in the lumenal domain. There is a small physicochemical difference between leucine and isoleucine. The variant is present in a large population cohort at a frequency of 0.1% (rs28937900, 168/152,176 alleles, 0 homozygotes in gnomAD v2.1), and is a European founder mutation 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 (PM3_VeryStrong, PP1_Strong; examples in PMID: 11741828, 15580560). Additionally, knock-in mouse models of the variant recapitulate the human phenotype (PS3; PMID: 23591631, 26574668). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/7 algorithms predict benign). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC . Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong.
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	RCV003914805	SCV004732345	pathogenic	FKRP-related condition	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