Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000559625 | SCV000630836 | pathogenic | Walker-Warburg congenital muscular dystrophy | 2023-10-18 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu55Cysfs*15) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 441 amino acid(s) of the FKRP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy or dystroglycanopathy (PMID: 12666124). ClinVar contains an entry for this variant (Variation ID: 459232). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Trp432*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002404397 | SCV002710102 | pathogenic | Cardiovascular phenotype | 2020-09-01 | criteria provided, single submitter | clinical testing | The c.158_162dupTGCGG pathogenic mutation, located in coding exon 1 of the FKRP gene, results from a duplication of TGCGG at nucleotide position 158, causing a translational frameshift with a predicted alternate stop codon (p.E55Cfs*15). This alteration occurs at the 3' terminus of theFKRP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 89% (442 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was detected as compound heterozygous with another variant in FKRP (p.W231C, c.693G>C) in an individual with congenital muscular dystrophy without mental retardation (Sframeli M et al. Neuromuscul. Disord., 2017 Sep;27:793-803). This variant was also detected as compound heterozygous with FKRP p.L276I (c.826C>A) in an individual with limb-girdle muscular dystrophy (LGMD) type 2I (Sveen ML et al. Ann. Neurol., 2006 May;59:808-15). In addition, this alteration was reported as compound heterozygous in two individuals with LGMD of unspecified type; however, the other FKRP variants were not described (Sframeli M et al. Neuromuscul. Disord., 2017 Sep;27:793-803). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Baylor Genetics | RCV003459205 | SCV004197395 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 | 2023-10-26 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV001834762 | SCV002088933 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2I | 2020-07-20 | no assertion criteria provided | clinical testing |