Submissions for variant NM_024301.5(FKRP):c.1384C>T (p.Pro462Ser)

gnomAD frequency: 0.00001  dbSNP: rs768606230

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671396	SCV000796368	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2017-12-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001573804	SCV002023715	pathogenic	not provided	2019-06-18	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000671396	SCV002761474	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2020-10-02	criteria provided, single submitter	clinical testing	The FKRP c.1384C>T missense variant is classified as LIKELY PATHOGENIC (PS4, PM3, PP3) The FKRP c.1384C>T missense variant is a single nucleotide change in exon 4 of the FKRP gene, which is predicted to change the amino acid proline at position 462 in the protein to serine. This variant has been reported in multiple patients with limb-girdle muscular dystrophy (PMID: 12666124, 16344347, 15883334, 30919934) (PS4). In these other patients, it has been detected in trans with a pathogenic variant in FKRP (PM3). This variant has been reported in dbSNP (rs768606230) but is rare in population databases (gnomAD allele frequency = 0.00092%, 2 het and 0 hom in 221310 sequenced alleles). This variant has been reported in ClinVar as likely pathogenic for Limb-girdle muscular dystrophy-dystroglycanopathy by another diagnostic laboratory (Variation ID: 555554). It is also reported as damaging for limb-girdle muscular dystrophy in the HGMD disease database (CM030975). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Invitae	RCV002531280	SCV003262053	pathogenic	Walker-Warburg congenital muscular dystrophy	2023-02-17	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 462 of the FKRP protein (p.Pro462Ser). This variant is present in population databases (rs768606230, gnomAD 0.002%). This missense change has been observed in individuals with FKRP-related conditions (PMID: 12666124, 15883334, 16344347, 30919934). ClinVar contains an entry for this variant (Variation ID: 555554). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323674	SCV004029701	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.1384C>T (p.Pro462Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-06 in 221310 control chromosomes (gnomAD). c.1384C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy (e.g. Mercuri_2003, Boito_2005, Sveen_2006, Juntas-Morales_2021). These data indicate that the variant is very likely to 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: 16344347, 34440373, 12666124, 16634037). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573804	SCV001800189	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001573804	SCV001809090	likely pathogenic	not provided		no assertion criteria provided	clinical testing