Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000543616 | SCV000630838 | uncertain significance | Walker-Warburg congenital muscular dystrophy | 2021-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 13 of the FKRP protein (p.Ala13Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs768376273, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002367797 | SCV002625420 | uncertain significance | Cardiovascular phenotype | 2019-08-29 | criteria provided, single submitter | clinical testing | The p.A13T variant (also known as c.37G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 37. The alanine at codon 13 is replaced by threonine, an amino acid with similar properties. An alternate amino acid substitution at this codon, p.A13S (c.37G>T) has been reported in an individual with myopathy, who also had an additional FKRP variant detected; however, clinical details were limited (Dai Y et al. Neuromuscul. Disord., 2015 Aug;25:617-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786132 | SCV000924794 | uncertain significance | not provided | 2017-05-02 | no assertion criteria provided | provider interpretation | Our patient had testing at the Invitae laboratory. Given the lack of case data, the fact that this is a heterozygous variant in a gene associated with autosomal recessive disease, and overall lack of gene-phenotype association, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The FKRP gene is associated with autosomal recessive muscular dystrophy and DCM. Our patient has only one heterozygous variant, and a phenotype of Afib. The variant has not been reported in any cases of FKRP-related disease. The variant is present in 1 individual listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant was observed in 1 of 16,627 individuals of Latino descent (MAF = 0.003%). The average coverage at that site in gnomAD is 30x. It should be noted that this variant is filtered out due to quality filters on first pass. |
| Natera, |
RCV001272533 | SCV001454623 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2I | 2020-09-16 | no assertion criteria provided | clinical testing |