Submissions for variant NM_024301.5(FKRP):c.1387A>G (p.Asn463Asp)

gnomAD frequency: 0.00002  dbSNP: rs121908110

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178346	SCV000230411	pathogenic	not provided	2016-06-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000194089	SCV000247379	pathogenic	Muscular dystrophy	2015-05-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540601	SCV000630832	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 463 of the FKRP protein (p.Asn463Asp). This variant is present in population databases (rs121908110, gnomAD 0.09%). This missense change has been observed in individual(s) with congenital muscular dystrophy and/or limb-girdle muscular dystrophy (PMID: 17336067; internal data database). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Mexican ancestry (PMID: 17336067; internal data database). ClinVar contains an entry for this variant (Variation ID: 4235). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FKRP protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001254718	SCV001430793	pathogenic	Muscular dystrophy-dystroglycanopathy type B5	2020-05-28	criteria provided, single submitter	research	The homozygous p.Asn463Asp variant in FKRP was identified by our study in an individual with muscular dystrophy-dystroglycanopathy (PMID: 31041397). The p.Asn463Asp variant has also been reported in at least 13 additional individuals with Hispanic or Mexican ancestry and muscular dystrophy-dystroglycanopathy, segregated with disease in 6 affected relatives from 3 families (PMID: 29065428, 31041397), and has been identified in 0.084% (27/32138) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908110). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported pathogenic by UChicago, EGL Genetic Diagnostics, Invitae, and OMIM in ClinVar (Variation ID: 4235). The presence of this variant in 9 affected homozygotes and in combination with a reported pathogenic variant and in 5 individuals with muscular dystrophy-dystroglycanopathy increases the likelihood that the p.Asn463Asp variant is pathogenic (PMID: 17336067, 29065428, 31041397, 31671740). In vitro functional studies provide some evidence that the p.Asn463Asp variant may impact protein function (PMID: 31041397). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for muscular dystrophy-dystroglycanopathy in an autosomal recessive manner based on the occurrence of this variant with other pathogenic variants in trans, functional evidence showing an affect to protein function, and segregation among multiple families. ACMG/AMP Criteria applied: PM3_Strong, PS3_moderate, PP1_strong, PP3 (Richards 2015).
GeneDx	RCV000178346	SCV001765021	pathogenic	not provided	2021-12-03	criteria provided, single submitter	clinical testing	Published functional study demonstrates c.1387A>G showed significantly decreased to absent glycosylated alpha-DG positivity with IIH6 antibody, and mild, variable decreases in beta-DG, dystrophin, and merosin (Lee et al., 2019); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 4235; ClinVar); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31041397, 17336067, 29065428, 31980526)
Revvity Omics, Revvity	RCV000178346	SCV002017776	likely pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490307	SCV002785332	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	2021-10-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114175	SCV003801181	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-01-28	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.1387A>G (p.Asn463Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 222240 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00012 vs 0.0024), allowing no conclusion about variant significance. c.1387A>G has been reported in the literature as a frequent founder variant of Mexican origin in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, PMID: 31931849, 31041397, 34653404). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although in one study, all muscle biopsies from homozygous individuals available for review showed end-stage dystrophic pathology, near absence of glycosylated alpha-dystroglycan (alpha-DG) by immunofluorescence, and reduced molecular weight of alpha-DG compared with controls (PMID: 31041397). Eight 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.
Baylor Genetics	RCV003460429	SCV004197414	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2024-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018553	SCV005028113	pathogenic	Cardiovascular phenotype	2024-02-23	criteria provided, single submitter	clinical testing	The p.N463D pathogenic mutation (also known as c.1387A>G), located in coding exon 1 of the FKRP gene, results from an A to G substitution at nucleotide position 1387. The asparagine at codon 463 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported in the homozygous state in multiple individuals with congenital muscular dystrophy, including hypotonia, motor delay, and elevated CK (MacLeod H et al. Neuromuscul. Disord., 2007 Apr;17:285-9; Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450; Lee AJ et al. Neurol Genet, 2019 Apr;5:e315). In addition, this variant has been reported in trans with a second FKRP alteration (Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450; Lee AJ et al. Neurol Genet, 2019 Apr;5:e315). It has been suggested that this might be a founder allele in individuals with Latino ancestry (Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450). Muscle biopsy from individuals homozygous for this alteration showed myopathic changes including variation in myofiber size, fatty replacement and endomysial fibrosis, absent alpha-dystroglycan staining, reduction in beta-dystroglycan as well as alpha-, beta-, and gamma-sarcoglycan staining, and mild focal reduction of dystrophin and merosin staining (MacLeod H et al. Neuromuscul. Disord., 2007 Apr;17:285-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV002226441	SCV000024630	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5	2007-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001273521	SCV001456658	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-09-16	no assertion criteria provided	clinical testing