ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.898G>A (p.Val300Met)

gnomAD frequency: 0.00016  dbSNP: rs563033008
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226616 SCV000290705 pathogenic Walker-Warburg congenital muscular dystrophy 2021-11-15 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 300 of the FKRP protein (p.Val300Met). 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 individual(s) with limb-girdle muscular dystrophy, and FKRP-related disorders (PMID: 14647208, 27848944; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 241460). 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. This variant disrupts the p.Val300 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647208, 15060126, 24447024). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Eurofins NTD LLC (GA) RCV000726141 SCV000342368 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000398763 SCV000594786 uncertain significance not specified 2015-11-16 criteria provided, single submitter clinical testing
Counsyl RCV000672226 SCV000797313 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2I 2018-01-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000726141 SCV000885462 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing The FKRP p.Val300Met variant (rs563033008) has been reported in the compound heterozygous state with a known pathogenic FKRP variant in two individuals who were diagnosed with limb girdle muscular dystrophy; however, inheritance information was not provided for these individuals (de Paula 2003, Frosk 2005, and Yamamoto 2008). The p.Val300Met variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.016% (identified in 5 out of 30,820 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 241460). The valine at codon 300 is highly conserved considering 11 species up to fruit fly (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FKRP protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, the available evidence is not sufficient to classify the p.Val300Met variant with certainty.
Fulgent Genetics,Fulgent Genetics RCV000765453 SCV000896744 uncertain significance 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 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000726141 SCV001815486 likely pathogenic not provided 2020-08-19 criteria provided, single submitter clinical testing Reported in an individual with limb girdle muscular dystrophy (LGMD) who also had a known pathogenic FKRP variant; however, information on the phase of the two variants was not provided (de Paula et al., 2003; Frosk et al., 2005; Yamamoto et al., 2008); This variant is associated with the following publications: (PMID: 15060126, 30564623, 27848944, 14647208, 15580560, 18645206, 24447024)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731540 SCV001983658 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy 2021-09-21 criteria provided, single submitter clinical testing Variant summary: FKRP c.898G>A (p.Val300Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 155330 control chromosomes (gnomAD and publication data). c.898G>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, including homozygotes (de Paula_2003, Trujillano_2017, Nallamilli_2018). These data indicate that the variant is likely to be associated with disease. Additionally, another missense variant at the same codon, V300A, was found in individuals affected with autosomal recessive limb-girdle muscular dystrophy, suggesting that this variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000726141 SCV002498488 likely pathogenic not provided 2022-03-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories,Mayo Clinic RCV000726141 SCV002520070 likely pathogenic not provided 2021-12-01 criteria provided, single submitter clinical testing PP3, PM2, PM3, PM5, PS4_supporting
MGZ Medical Genetics Center RCV000672226 SCV002581281 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2022-02-28 criteria provided, single submitter clinical testing

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