ClinVar

Description

The FKRP c.162_165dup; p.Phe56GlyfsTer6 variant (rs886042506; also reported as 165InsGGAG; ClinVar Variation ID: 282866), has been previously identified in trans with other pathogenic variants in FKRP in at least two patients with symptoms of congenital muscular dystrophy and reduced glycosylated alpha-dystroglycan (Brockington 2001 and Peat 2008). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last (and only coding) exon of the FKRP gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 6 amino acid residues not usually present. Additionally, several downstream truncating variants have been described in individuals with FKRP-related muscular dystrophy and are considered pathogenic (Selected references: Brockington 2001 and Matsumoto 2005). Based on the available information, the p.Phe56GlyfsTer6 variant is considered pathogenic. References: Brockington M et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001 Dec;69(6):1198-209. PMID: 11592034 Matsumoto H et al. Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan. Neuromuscul Disord. 2005 May;15(5):342-8. PMID: 15833426. Peat RA et al. Diagnosis and etiology of congenital muscular dystrophy. Neurology. 2008 Jul 29;71(5):312-21. PMID: 18160674.