Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000360542 | SCV000345061 | pathogenic | not provided | 2017-12-14 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000763056 | SCV000893537 | likely pathogenic | 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 | 2022-02-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002381242 | SCV002688773 | likely pathogenic | Cardiovascular phenotype | 2022-07-14 | criteria provided, single submitter | clinical testing | The p.P448L variant (also known as c.1343C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 1343. The proline at codon 448 is replaced by leucine, an amino acid with similar properties. This alteration has been reported as homozygous in an individual with congenital muscular dystrophy (Brockington M et al. Am J Hum Genet, 2001 Dec;69:1198-209). Additionally, both in vitro and in vivo assays showed this alteration impacts protein function, including a homozygous knock-in mouse that showed this alteration almost completely lacks functional glycosylation of alpha-dystroglycan in muscles and brain (Esapa CT et al. Hum Mol Genet, 2002 Dec;11:3319-31; Esapa CT et al. Hum Mol Genet, 2005 Jan;14:295-305; Keramaris-Vrantsis E et al. Muscle Nerve, 2007 Oct;36:455-65; Lu PJ et al. Biochim Biophys Acta, 2010 Feb;1802:253-8; Chan YM et al. Hum Mol Genet, 2010 Oct;19:3995-4006; Maricelli JW et al. PLoS One, 2016 Sep;11:e0161984; Blaeser A et al. PLoS One, 2016 Oct;11:e0164187). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Ce |
RCV000360542 | SCV004011082 | pathogenic | not provided | 2023-05-01 | criteria provided, single submitter | clinical testing | FKRP: PM3:Strong, PM2, PS3:Moderate, PP3, PP4 |
| Baylor Genetics | RCV003466807 | SCV004197415 | likely pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 | 2023-08-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003591620 | SCV004276080 | pathogenic | Walker-Warburg congenital muscular dystrophy | 2023-05-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 12471058, 15574464, 19900540, 20675713, 27711214, 29858056, 30417025). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function. ClinVar contains an entry for this variant (Variation ID: 4220). This missense change has been observed in individuals with muscular dystrophy (PMID: 11592034, 31069529). This variant is present in population databases (rs104894681, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 448 of the FKRP protein (p.Pro448Leu). |
| OMIM | RCV002226440 | SCV000024614 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5 | 2001-12-01 | no assertion criteria provided | literature only |