ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.205T>C (p.Ser69Pro)

gnomAD frequency: 0.00001  dbSNP: rs990847012
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001295759 SCV001484704 likely pathogenic Walker-Warburg congenital muscular dystrophy 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 69 of the FKRP protein (p.Ser69Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 999725). 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 with a positive predictive value of 95%. This variant disrupts the p.Ser69 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27142102, 27439679). 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.
Ambry Genetics RCV002418887 SCV002724772 uncertain significance Cardiovascular phenotype 2019-03-20 criteria provided, single submitter clinical testing The p.S69P variant (also known as c.205T>C), located in coding exon 1 of the FKRP gene, results from a T to C substitution at nucleotide position 205. The serine at codon 69 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002493553 SCV002779789 uncertain significance 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 2021-09-23 criteria provided, single submitter clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System RCV001830129 SCV003919048 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2I 2023-04-20 criteria provided, single submitter research
Natera, Inc. RCV001830129 SCV002088938 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2I 2021-10-04 no assertion criteria provided clinical testing

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