ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.898G>A (p.Val300Met) (rs563033008)

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Total submissions: 6
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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 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 300 of the FKRP protein (p.Val300Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with limb-girdle muscular dystrophy (Invitae). This variant has also been observed to be homozygous or in combination with another FKRP variant in individuals affected with FKRP-related disorders (PMID: 14647208, 27848944). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 241460). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Val300 amino acid residue in FKRP have been observed in affected individuals (PMID: 14647208, 15060126, 24447024). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 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 A, 1; Congenital muscular dystrophy-dystroglycanopathy (with or without mental retardation) type B5; Limb-girdle muscular dystrophy-dystroglycanopathy, type C5; Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A5 2018-10-31 criteria provided, single submitter clinical testing

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