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

gnomAD frequency: 0.00011  dbSNP: rs143031195

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657079	SCV000202717	uncertain significance	not provided	2016-06-27	criteria provided, single submitter	clinical testing
Invitae	RCV000473789	SCV000548513	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 358 of the FKRP protein (p.Pro358Leu). This variant is present in population databases (rs143031195, gnomAD 0.2%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 14647208, 16344347, 17952692; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167072). 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%. For these reasons, this variant has been classified as 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.
Baylor Genetics	RCV001336093	SCV001529389	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2018-08-29	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
New York Genome Center	RCV001838983	SCV002099321	likely pathogenic	Muscular dystrophy-dystroglycanopathy type B5; Autosomal recessive limb-girdle muscular dystrophy type 2I; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2023-05-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288663	SCV002579175	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2021-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298484	SCV002598950	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-09-01	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.1073C>T (p.Pro358Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 213340 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00014 vs 0.0024), allowing no conclusion about variant significance. c.1073C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive or FKRP-related disorders. Multiple patients also carry another pathogenic FKRP variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002415648	SCV002721794	uncertain significance	Cardiovascular phenotype	2023-03-15	criteria provided, single submitter	clinical testing	The p.P358L variant (also known as c.1073C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 1073. The proline at codon 358 is replaced by leucine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with additional alterations in FKRP in individuals with concerns for muscular dystrophies, including limb girdle muscular dystrophy; however, clinical details were limited in some cases (de Paula F et al. Eur J Hum Genet, 2003 Dec;11:923-30; Boito CA et al. Arch Neurol, 2005 Dec;62:1894-9; Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803; Wu L et al. Can J Neurol Sci, 2018 May;45:262-268; Murphy LB et al. Ann Clin Transl Neurol, 2020 May;7:757-766; Krenn M et al. Eur J Neurol, 2022 Jun;29:1815-1824; Gonzalez-Perez P et al. Neuromuscul Disord, 2020 Mar;30:213-218). 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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV002288663	SCV002764703	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-11-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000657079	SCV003832623	uncertain significance	not provided	2019-03-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288663	SCV003841219	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I		criteria provided, single submitter	clinical testing
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.