Submissions for variant NM_024301.5(FKRP):c.934C>G (p.Arg312Gly)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002593065	SCV002939384	likely pathogenic	Walker-Warburg congenital muscular dystrophy	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 312 of the FKRP protein (p.Arg312Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 37526466). ClinVar contains an entry for this variant (Variation ID: 1910167). 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%. This variant disrupts the p.Arg312 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11741828; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224635	SCV003919966	uncertain significance	Muscular dystrophy-dystroglycanopathy type B5; Autosomal recessive limb-girdle muscular dystrophy type 2I; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2021-03-30	criteria provided, single submitter	clinical testing	FKRP NM_024301.4 exon 4 p.Arg312Gly (c.934C>G): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801225	SCV005423278	uncertain significance	not specified	2024-10-30	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.934C>G (p.Arg312Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 160526 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.934C>G has been reported in the literature in at least an individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Zidkova_2023). This report however, does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37526466). ClinVar contains an entry for this variant (Variation ID: 1910167). Based on the evidence outlined above, the variant was classified as uncertain significance.