Submissions for variant NM_024301.5(FKRP):c.563C>T (p.Ala188Val)

gnomAD frequency: 0.00006  dbSNP: rs768762059

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489382	SCV000577046	uncertain significance	not specified	2017-04-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FKRP gene. The A188V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, the A188V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Genetic Services Laboratory, University of Chicago	RCV000489382	SCV000594780	uncertain significance	not specified	2015-12-31	criteria provided, single submitter	clinical testing
Invitae	RCV001242700	SCV001415803	uncertain significance	Walker-Warburg congenital muscular dystrophy	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the FKRP protein (p.Ala188Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FKRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 426570). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002350087	SCV002654240	uncertain significance	Cardiovascular phenotype	2022-06-22	criteria provided, single submitter	clinical testing	The p.A188V variant (also known as c.563C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 563. The alanine at codon 188 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002475962	SCV002775849	uncertain significance	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	2021-10-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003144287	SCV003832644	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001834588	SCV002088961	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-12-01	no assertion criteria provided	clinical testing