Submissions for variant NM_024301.5(FKRP):c.1267del (p.Arg423fs)

dbSNP: rs886044083

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000376382	SCV000343381	pathogenic	not provided	2016-07-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272206	SCV002557699	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy; with congenital with brain and eye anomalies (MIM#613153), with or without intellectual disability type B (MIM#606612), limb-girdle type C (MIM#607155). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other downstream truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least three others have been reported in ClinVar and one other in a patient with limb girdle muscular dystrophy (ClinVar; PMID: 16288869). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It was found in a limb girdle muscular dystrophy patient compound heterozygous with a pathogenic missense variant (PMID: 30564623). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV003754873	SCV004535480	pathogenic	Walker-Warburg congenital muscular dystrophy	2023-04-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FKRP protein in which other variant(s) (p.Ile478Thr) have been determined to be pathogenic (PMID: 16476814, 18639457, 19299310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 289096). This premature translational stop signal has been observed in individual(s) with clinical features of FKRP-related conditions (PMID: 30564623). This sequence change creates a premature translational stop signal (p.Arg423Alafs*5) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the FKRP protein.