Submissions for variant NM_024301.5(FKRP):c.1433T>C (p.Ile478Thr)

gnomAD frequency: 0.00001  dbSNP: rs1301397800

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000634073	SCV000755351	pathogenic	Walker-Warburg congenital muscular dystrophy	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 478 of the FKRP protein (p.Ile478Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with congenital muscular dystrophy (PMID: 16476814, 18639457, 19299310). ClinVar contains an entry for this variant (Variation ID: 528825). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000671168	SCV000796118	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2017-12-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731349	SCV000859155	pathogenic	not provided	2018-01-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000731349	SCV003833416	likely pathogenic	not provided	2022-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459515	SCV004197393	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2023-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488744	SCV004241958	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.1433T>C (p.Ile478Thr) 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 4.1e-06 in 245556 control chromosomes (gnomAD). c.1433T>C has been reported in the literature in multiple individuals affected with Muscular Dystrophy, Autosomal Recessive (examples: Mercuri_2006, Wahbi_2008, Leung_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16476814, 18639457, 32429923). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.