Submissions for variant NM_024301.5(FKRP):c.740C>A (p.Pro247Gln)

gnomAD frequency: 0.00124  dbSNP: rs528000488

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711665	SCV000202716	uncertain significance	not provided	2018-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079526	SCV000548526	likely benign	Walker-Warburg congenital muscular dystrophy	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000711665	SCV000582234	likely benign	not provided	2021-04-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711665	SCV000842052	uncertain significance	not provided	2018-12-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000711665	SCV001473933	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	The FKRP c.740C>A; p.Pro247Gln variant (rs528000488), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 167071). This variant is found in the African population with an allele frequency of 0.42% (38/9132 alleles) in the Genome Aggregation Database. The proline at codon 247 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Pro247Gln variant is uncertain at this time.
Ambry Genetics	RCV002381484	SCV002673101	likely benign	Cardiovascular phenotype	2022-05-04	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	RCV000711665	SCV003832657	likely benign	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225033	SCV003921956	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2020-07-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine (exon 4). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 172 heterozygotes, 0 homozygotes. (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. A different variant in the same codon resulting in a change to arginine has been reported as a variant of uncertain significance in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a variant of uncertain significance and likely benign in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000711665	SCV004225414	uncertain significance	not provided	2021-11-29	criteria provided, single submitter	clinical testing	BS1
Natera, Inc.	RCV001275315	SCV001460340	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2I	2019-12-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544393	SCV004767945	likely benign	FKRP-related disorder	2022-02-27	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).