ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.266C>T (p.Pro89Leu)

gnomAD frequency: 0.00002  dbSNP: rs770711331
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665956 SCV000790174 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2017-03-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000700227 SCV000828975 pathogenic Walker-Warburg congenital muscular dystrophy 2024-02-04 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 89 of the FKRP protein (p.Pro89Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with muscular dystrophy (PMID: 16368217, 17446099, 18639457, 18691338). ClinVar contains an entry for this variant (Variation ID: 551007). 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.Pro89 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been observed in individuals with FKRP-related conditions (PMID: 15833426, 17113772), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001784236 SCV002017778 likely pathogenic not provided 2021-07-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002499150 SCV002809819 likely pathogenic 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 2021-10-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV004568497 SCV005057786 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 2024-02-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV004993923 SCV005581234 pathogenic Cardiovascular phenotype 2024-10-16 criteria provided, single submitter clinical testing The p.P89L pathogenic mutation (also known as c.266C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 266. The proline at codon 89 is replaced by leucine, an amino acid with similar properties. This variant has been identified in the homozygous state and/or in conjunction with other FKRP variant(s) in individual(s) with features consistent with FKRP-related dystroglycanopathies (Vieira NM et al. Neuromuscul Disord, 2006 Dec;16:870-3; Quijano-Roy S et al. Brain Dev, 2006 May;28:232-42; Darin N et al. Eur J Paediatr Neurol, 2007 Nov;11:353-7; Wahbi K et al. Neuromuscul Disord, 2008 Aug;18:650-5; Jimenez-Mallebrera C et al. Brain Pathol, 2009 Oct;19:596-611; Carlson CR et al. Neurology, 2017 Dec;89:2374-2380; Murphy LB et al. Ann Clin Transl Neurol, 2020 May;7:757-766; Nallamilli BRR et al. Ann Clin Transl Neurol, 2023 Nov;10:2092-2104). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Natera, Inc. RCV000665956 SCV001454628 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2020-09-16 no assertion criteria provided clinical testing

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