Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000004449 | SCV000800282 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2I | 2018-05-30 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV000004449 | SCV003841443 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2I | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.58). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004228 / PMID: 14523375). Different missense changes at the same codon (p.Arg54Gln, p.Arg54Gly) have been reported to be associated with FKRP related disorder (ClinVar ID: VCV001524557 / PMID: 27439679, 33200426). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Invitae | RCV003591622 | SCV004298418 | pathogenic | Walker-Warburg congenital muscular dystrophy | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 54 of the FKRP protein (p.Arg54Trp). 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: 14523375, 30003095). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4228). 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 80%. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000004449 | SCV000024622 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2I | 2004-01-01 | no assertion criteria provided | literature only |