rs770711331
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_024301.5(FKRP):c.266C>T(p.Pro89Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000913 in 1,424,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89A) has been classified as Pathogenic.
Frequency
Consequence
NM_024301.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.266C>T | p.Pro89Leu | missense_variant | 4/4 | ENST00000318584.10 | NP_077277.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.266C>T | p.Pro89Leu | missense_variant | 4/4 | 1 | NM_024301.5 | ENSP00000326570.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000154 AC: 3AN: 195042Hom.: 0 AF XY: 0.0000187 AC XY: 2AN XY: 106826
GnomAD4 exome AF: 0.00000913 AC: 13AN: 1424412Hom.: 0 Cov.: 33 AF XY: 0.00000848 AC XY: 6AN XY: 707232
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 07, 2017 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 09, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 30, 2021 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at