Submissions for variant NM_024301.5(FKRP):c.1154C>T (p.Ser385Leu)

gnomAD frequency: 0.00086  dbSNP: rs104894680

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000285599	SCV000345878	uncertain significance	not provided	2017-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079454	SCV000630827	likely benign	Walker-Warburg congenital muscular dystrophy	2025-01-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000285599	SCV001475115	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348030	SCV002623291	likely benign	Cardiovascular phenotype	2023-04-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000285599	SCV003832614	uncertain significance	not provided	2021-02-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000285599	SCV003923352	uncertain significance	not provided	2024-08-05	criteria provided, single submitter	clinical testing	Previously reported as heterozygous in an individual with suspected limb girdle muscular dystrophy (PMID: 30564623); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 32906206, 27439679, 30564623)
Mayo Clinic Laboratories, Mayo Clinic	RCV000285599	SCV005408874	uncertain significance	not provided	2024-02-29	criteria provided, single submitter	clinical testing	PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238861	SCV005885760	likely benign	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.1154C>T (p.Ser385Leu) 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 0.00013 in 1611398 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0024). c.1154C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Nallamilli_2018). These report(s) do 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. The following publication have been ascertained in the context of this evaluation (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 291171). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004537622	SCV004745875	likely benign	FKRP-related disorder	2022-09-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).