ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.1073C>T (p.Pro358Leu) (rs143031195)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000657079 SCV000202717 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing
Invitae RCV000473789 SCV000548513 likely pathogenic Walker-Warburg congenital muscular dystrophy 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 358 of the FKRP protein (p.Pro358Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs143031195, ExAC 0.05%). This variant has been observed in individuals affected with limb-girdle muscular dystrophy (PMID: 14647208, 16344347, 17952692, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167072). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000657079 SCV000568369 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing The P358L variant of uncertain significance has been previously described in association with LGMD2I (de Paula et al., 2003; Boito et al., 2005, Boito et al., 2007; Palmieri et al., 2011). In these published cases, P358L was reportedly observed in both the homozygous and compound heterozygous state with another FKRP variant, although parental testing confirming autosomal recessive inheritance was not described. The P358L variant is observed in 22/9258 (0.2%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The P358L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000657079 SCV000924796 uncertain significance not provided 2017-04-05 no assertion criteria provided provider interpretation p.Pro358Leu (c.1073C>T) in the FKRP gene. This variant was seen in a patient in our clinic with atrial fibrillation. Testing was performed at Invitae. Given the lack of known gene-phenotype association, lack of case data, and overall frequency in the general population, we consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). At this time there is no data to connect it to atrial fibrillation that we are aware of. It may be an autosomal recessive allele for muscular dystrophy, however Invitae currently considers it a variant of uncertain significance even for that. There is an entry in ClinVar from Emory; it is classified by themas variant of uncertain significance. Per the lab report, "The FKRP gene is associated with autosomal recessive muscular dystrophy-dystroglycanopathy type A5 (MDDGA5) (MedGen UID:461763), type B5 (MDDGB5) (MedGen UID:335764), and type C5) (MedGen UID:339580), and dilated cardiomyopathy (DCM) (MedGen UID:2880)." The lab report notes that the variant has been reported in multiple individuals with limb girdle muscular dystrophy (LGMD), however the frequency in the general population raises the question of whether this could be a benign ethnicity-specific variant (see below). Boito et al. (2005) observed the variant in 3 of 214 patients recruited in Italy and both were compound heterozygotes, consistent with the autosomal recessive inheritance previously reported for FKRP in LGMD. De Paula et al. (2003) also reported a compound heterozygote for this variant who had LGMD (recruited in Brazil). Per the lab report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably"; Align-GVGD: "Class C0")." The variant was reported online in 32 of 119,683 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The absence of calls for 20,000 individuals in gnomAD may indicate that it is a low-quality site. It is by far most common in Ashkenazi Jewish individuals, such as our patient. Specifically, the variant was observed in 22/4,629 Ashkenazi Jewish individuals, for an ethnicity-specific allele frequency of 0.24%. (This would predict an autosomal recessive disease prevalence of ~1/175,000.) It was also observed in 6 non-Finnish Europeans, 2 “Other” ancestry, 1 African, and 1 Latino. Overall allele frequency: 0.013%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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