chr19-46756181-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024301.5(FKRP):c.731G>A(p.Arg244His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,439,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024301.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.731G>A | p.Arg244His | missense_variant | Exon 4 of 4 | ENST00000318584.10 | NP_077277.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.731G>A | p.Arg244His | missense_variant | Exon 4 of 4 | 1 | NM_024301.5 | ENSP00000326570.4 | ||
FKRP | ENST00000391909.7 | c.731G>A | p.Arg244His | missense_variant | Exon 4 of 4 | 2 | ENSP00000375776.2 | |||
FKRP | ENST00000597339.5 | n.247-5652G>A | intron_variant | Intron 3 of 3 | 5 | |||||
FKRP | ENST00000600646.5 | n.247+7516G>A | intron_variant | Intron 3 of 3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000258 AC: 39AN: 151140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000348 AC: 20AN: 57478Hom.: 0 AF XY: 0.000294 AC XY: 10AN XY: 34034
GnomAD4 exome AF: 0.000111 AC: 143AN: 1288044Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 72AN XY: 633324
GnomAD4 genome AF: 0.000258 AC: 39AN: 151248Hom.: 0 Cov.: 33 AF XY: 0.000203 AC XY: 15AN XY: 73914
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 12, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 10, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2021 | Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (Boito et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 16344347, 26990548, 17952692, 30564623) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2023 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2025 | Variant summary: FKRP c.731G>A (p.Arg244His) results in a non-conservative amino acid change located in the fukutin-related protein stem domain (IPR055105) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 57478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKRP causing Autosomal recessive limb-girdle muscular dystrophy type 2I (0.00035 vs 0.011), allowing no conclusion about variant significance. c.731G>A has been reported in the literature in at least one homozygous individual affected with Autosomal recessive limb-girdle muscular dystrophy type 2I (e.g., Boito_2005, Boito_2007), without strong evidence for causality. These data indicate that the variant may be associated with disease. Muscle biopsy analysis of this homozygous patient showed conflicting results indicating that glycosylated alpha-dystroglycan levels were possibly (but not clearly) decreased vs. controls (Boito_2005, Boito_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17952692, 16344347). ClinVar contains an entry for this variant (Variation ID: 283038). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 30, 2016 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2I Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 16, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 12, 2020 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2024 | The p.R244H variant (also known as c.731G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 731. The arginine at codon 244 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a homozygous individual with limb girdle muscular dystrophy, including myalgia, more affected lower limbs than upper, and no muscle hypertrophy; muscle biopsy results showed some reduction in glycosylated alpha-dystroglycan expression compared to controls (Boito CA et al. Arch. Neurol., 2005 Dec;62:1894-9; Boito CA et al. Virchows Arch., 2007 Dec;451:1047-55). 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. - |
Walker-Warburg congenital muscular dystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 01, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at