rs758759348
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP5BP4
The NM_024301.5(FKRP):c.328C>T(p.Arg110Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,528,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110P) has been classified as Uncertain significance.
Frequency
Consequence
NM_024301.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.328C>T | p.Arg110Trp | missense_variant | 4/4 | ENST00000318584.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.328C>T | p.Arg110Trp | missense_variant | 4/4 | 1 | NM_024301.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152136Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000104 AC: 14AN: 134338Hom.: 0 AF XY: 0.000122 AC XY: 9AN XY: 73588
GnomAD4 exome AF: 0.0000131 AC: 18AN: 1376664Hom.: 0 Cov.: 32 AF XY: 0.0000133 AC XY: 9AN XY: 677866
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74430
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21296577, 18036232, 25135358) - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 110 of the FKRP protein (p.Arg110Trp). This variant is present in population databases (rs758759348, gnomAD 0.1%). This missense change has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 18036232, 25135358, 33200426; Invitae). ClinVar contains an entry for this variant (Variation ID: 408718). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FKRP protein function. This variant disrupts the p.Arg110 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been observed in individuals with FKRP-related conditions (PMID: 16368217), which suggests that this may be a clinically significant amino acid residue. 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. - |
Autosomal recessive limb-girdle muscular dystrophy type 2I Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2023 | The p.R110W variant (also known as c.328C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by tryptophan, an amino acid with dissimilar properties. This variant co-occurred with other FKRP variants in individuals reported to have limb-girdle muscular dystrophy phenotype; however, phase determination was not always clear and/or clinical details were limited (Kang PB et al. BMC Musculoskelet Disord, 2007 Nov;8:115; Song D et al. Clin Genet. 2021 Mar;99(3):384-395; Jensen SM et al. Neuromuscul Disord. 2023 Feb;33(2):119-132). This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at