Submissions for variant NM_024301.5(FKRP):c.731G>A (p.Arg244His)

gnomAD frequency: 0.00010  dbSNP: rs764641619

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725201	SCV000334847	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457561	SCV000548508	likely benign	Walker-Warburg congenital muscular dystrophy	2024-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000331999	SCV000594784	uncertain significance	not specified	2016-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000725201	SCV000617404	uncertain significance	not provided	2021-02-13	criteria provided, single submitter	clinical testing	Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (Boito et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 16344347, 26990548, 17952692, 30564623)
Counsyl	RCV000664793	SCV000788808	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2I	2016-12-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725201	SCV001250132	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000725201	SCV001475118	uncertain significance	not provided	2019-11-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000331999	SCV002598949	uncertain significance	not specified	2022-09-17	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.731G>A (p.Arg244His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 149914 control chromosomes (gnomAD v3.1.2), predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00026 vs 0.0024), allowing no conclusion about variant significance. c.731G>A has been reported in the literature in at least one homozygous individual affected with mild Limb-Girdle Muscular Dystrophy (Boito_2005, Boito_2007). These data indicate that the variant may be associated with disease. Muscle biopsy analysis of this homozygous patient showed that glycosylated alpha-dystroglycan levels were 20% of what is seen in controls (Boito_2007). Eight ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV002379117	SCV002671039	uncertain significance	Cardiovascular phenotype	2024-01-19	criteria provided, single submitter	clinical testing	The p.R244H variant (also known as c.731G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 731. The arginine at codon 244 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a homozygous individual with limb girdle muscular dystrophy, including myalgia, more affected lower limbs than upper, and no muscle hypertrophy; muscle biopsy results showed some reduction in glycosylated alpha-dystroglycan expression compared to controls (Boito CA et al. Arch. Neurol., 2005 Dec;62:1894-9; Boito CA et al. Virchows Arch., 2007 Dec;451:1047-55). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000725201	SCV003832608	uncertain significance	not provided	2023-11-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000664793	SCV001460339	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-01-12	no assertion criteria provided	clinical testing