Submissions for variant NM_024301.5(FKRP):c.350C>G (p.Pro117Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593341	SCV004298419	likely pathogenic	Walker-Warburg congenital muscular dystrophy	2022-11-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 missense change has been observed in individual(s) with muscular congenital dystrophy type 1C (PMID: 27439679, 30210031). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 117 of the FKRP protein (p.Pro117Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690437	SCV005184666	uncertain significance	not specified	2024-05-14	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.350C>G (p.Pro117Arg) 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 120542 control chromosomes. c.350C>G has been reported in the literature in at-least two individuals affected withCongenital muscular dystrophy type 1C (Fu_2016, Hong_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27439679, 30210031). ClinVar contains an entry for this variant (Variation ID: 2736910). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.