Submissions for variant NM_024301.5(FKRP):c.280C>T (p.Pro94Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002510258	SCV002819752	uncertain significance	not specified	2022-12-22	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.280C>T (p.Pro94Ser) results in a non-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 was absent in 182826 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.280C>T has been reported in the literature in one heterozygous individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Guglieri_2007) in the absence of another variant. This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002569429	SCV003443400	uncertain significance	Walker-Warburg congenital muscular dystrophy	2022-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 94 of the FKRP protein (p.Pro94Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 17994539). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.