ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.1486T>A (p.Ter496Arg)

gnomAD frequency: 0.00001  dbSNP: rs104894682
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000725596 SCV000338011 pathogenic not provided 2017-04-25 criteria provided, single submitter clinical testing
Invitae RCV000471321 SCV000548504 pathogenic Walker-Warburg congenital muscular dystrophy 2023-12-18 criteria provided, single submitter clinical testing This sequence change disrupts the translational stop signal of the FKRP mRNA. It is expected to extend the length of the FKRP protein by 21 additional amino acid residues. This variant is present in population databases (rs104894682, gnomAD 0.0009%). This protein extension has been observed in individuals with limb girdle muscular dystrophy (PMID: 10838249, 12707439, 15060126, 18671187). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4223). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000501528 SCV000594787 likely pathogenic Muscular dystrophy-dystroglycanopathy 2017-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222339 SCV002500248 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2022-03-01 criteria provided, single submitter clinical testing Variant summary: FKRP c.1486T>A (p.X496ArgextX21) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 8.1e-06 in 245964 control chromosomes (gnomAD). c.1486T>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy and vacuolar myopathy (examples: Driss_2003, Kefi_2008, Mair_2020, Walter_FKRP_2004). The variant also seggregated with disease. These data indicate that the variant is very likely to be associated with disease. Driss_2003 demonstrated that this variant reduced alpha dystroglycan and laminin levels in isolated muscle protein immmunoblots. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004444 SCV000024617 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2003-04-22 no assertion criteria provided literature only
Natera, Inc. RCV000004444 SCV002091359 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2I 2020-09-09 no assertion criteria provided clinical testing

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