rs28937900

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

The NM_024301.5(FKRP):c.826C>A(p.Leu276Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,516,960 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 2 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:44

Conservation

PhyloP100: 1.80

Variant links:

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a strand (size 3) in uniprot entity FKRP_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_024301.5

PP5

Variant 19-46756276-C-A is Pathogenic according to our data. Variant chr19-46756276-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756276-C-A is described in Lovd as [Pathogenic]. Variant chr19-46756276-C-A is described in Lovd as [Pathogenic]. Variant chr19-46756276-C-A is described in Lovd as [Likely_pathogenic]. Variant chr19-46756276-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.009812146). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.826C>A	p.Leu276Ile	missense_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.826C>A	p.Leu276Ile	missense_variant	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.826C>A	p.Leu276Ile	missense_variant	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5557C>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7611C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000476

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00103

AC:

125

AN:

121630

Hom.:

AF XY:

0.00108

AC XY:

AN XY:

66754

show subpopulations

Gnomad AFR exome

AF:

0.000158

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.00207

AC:

2826

AN:

1365112

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1356

AN XY:

672092

show subpopulations

Gnomad4 AFR exome

AF:

0.000387

Gnomad4 AMR exome

AF:

0.000328

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00147

Gnomad4 NFE exome

AF:

0.00251

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

151848

Hom.:

Cov.:

AF XY:

0.000997

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000476

Gnomad4 NFE

AF:

0.00201

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000813

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000662

AC:

ExAC

AF:

0.000925

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:44

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:16

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 19, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 08, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FKRP: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 18, 2017	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jul 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Feb 28, 2022	ACMG categories: PS1,PS5,PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 17, 2023	Criteria applied: PM3_VSTR,PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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 ÃŽÂ±-dystroglycan specific glycosylation (Krag 2015 PMID:26574668). In summary, this variant is classified as pathogenic. -

Limb-girdle muscular dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, University of Wuerzburg	-	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	May 21, 2021	• 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] -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2022

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. -

Headache;C0030554:Paresthesia;C0151786:Muscle weakness;C0239067:Difficulty climbing stairs;C0240953:Scapular winging;C0241237:Difficulty standing;C0311394:Difficulty walking;C1836150:Gait imbalance

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 31, 2022

- -

FKRP-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

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. -

Muscular dystrophy-dystroglycanopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 20, 2016

- -

Muscular dystrophy-dystroglycanopathy type B5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 24, 2018

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

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. -

Walker-Warburg congenital muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

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. -

Myopathy caused by variation in FKRP

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.39

T;T

Eigen

Benign

0.049

Eigen_PC

Benign

0.058

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.53

.;T

MetaRNN

Benign

0.0098

T;T

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.85

N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.065

T;T

Sift4G

Benign

0.066

T;T

Polyphen

0.85

P;P

Vest4

0.56

MVP

0.87

MPC

1.2

ClinPred

0.025

GERP RS

4.2

Varity_R

0.47

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over