Submissions for variant NM_024301.5(FKRP):c.731G>A (p.Arg244His) (rs764641619)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000725201	SCV000334847	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV000457561	SCV000548508	uncertain significance	Walker-Warburg congenital muscular dystrophy	2019-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 244 of the FKRP protein (p.Arg244His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in homozygous state in an individual affected with Limb-Girdle Muscular Dystrophy Type 2I and the muscle biopsy of the patient showed that the functional glycosylation of -dystroglycan was approximately 20% of control levels (PMID: 16344347, 17952692). ClinVar contains an entry for this variant (Variation ID: 283038). 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 histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
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	2018-07-23	criteria provided, single submitter	clinical testing	The R244H variant has been reported previously in the homozygous state in a patient with LGMD2I (Boito et al., 2005). Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (Boito et al., 2007). The R244H variant is observed in 8/9,428 (0.08%) alleles from individuals of Latino background (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Counsyl	RCV000664793	SCV000788808	uncertain significance	Limb-girdle muscular dystrophy-dystroglycanopathy, type C5	2016-12-16	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000725201	SCV001250132	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing